INDRA Results

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Dabrafenib inhibits mutated BRAF. 10 / 10

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"On the other hand, vemurafenib and dabrafenib inhibit mutations of BRAF V600, which prevents oncogenic activities such as proliferation and evasion of immune response."

25801067

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"Dabrafenib is a potent inhibitor of mutant BRAF."

25711514

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"Tyrosine kinase inhibitors (TKI) such as gefitinib, osimertinib, and erlotinib target EGFR mutations found in lung cancers, lapatinib is a dual TKI that targets HER2 and neu and EGFR mutations and is applied to advanced or metastatic breast cancer, vemurafenib and dabrafenib target BRAF mutations in melanoma, and crizotinib, ceritinib, and alectinib target anaplastic lymphoma kinase fusions in lung cancers."

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"Both drugs target the mitogen activated protein kinase (MAPK) pathway : dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases."

24583796

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"Dabrafenib inhibits the mutant BRAF (BRAF mut) protein in melanomas with BRAF V600E and BRAF V600K genotypes."

23251089

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"Gene therapy Vemurafenib and dabrafenib are potent inhibitors of the kinase domain in mutant BRAF, approved for the treatment of metastatic melanoma with a V600E BRAF mutation."

27974909

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"BRAF inhibitors vemurafenib and dabrafenib, selectively block the mutant BRAF protein and prolong overall survival in patients with BRAF mutant melanoma [XREF_BIBR, XREF_BIBR]."

26771141

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"Dabrafenib inhibited BRAF mutant cell lines with a 284 times lower IC 50 than non mutant cell lines."

24651269

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"Dabrafenib (GSK2118436) is a selective inhibitor of mutant BRAF."

24432031

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"Although mutant BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors such as vemurafenib and dabrafenib have achieved unprecedented clinical responses in the treatment of melanomas with activating mutations in BRAF, complete remission is rare and a proportion of mutant BRAF melanomas are less responsive to the inhibitors."

23744355

Dabrafenib inhibits BRAF-V600E. 10 / 10

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"Vemurafenib and dabrafenib selectively inhibit the BRAF V600E oncoprotein, thereby inhibiting this pathway that is important in melanoma tumorigenesis."

25037801

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"While treatment with selective BRAF (V600E) inhibitors (like vemurafenib or dabrafenib) leads to high response rates but short response duration, CTLA-4 blocking therapies induce sustained responses, but only in a limited number of patients."

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"If the BRAF V600E mutation is present, as determined by sequencing or mutation specific PCR based assays, patients are eligible to receive a BRAF V600E -selective inhibitor such as vemurafenib or dabrafenib."

23483066

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"Vemurafenib and other BRAF V600E inhibitors like dabrafenib (GlaxoSmithKline, currently in Phase III trials) inhibit the BRAF V600E monomer but are unable to block ligand mediated RAF-RAF dimers."

24312896

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"The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. 46999999="V600E"}"

24901049

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"Although BRAF V600E -specific inhibitors such as vemurafenib and dabrafenib have only recently entered clinical practice for children whose tumors carry this mutation, initial reports are encouraging."

27217440

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"The reversible B-Raf inhibitor, dabrafenib (GSK2118436), which selectively inhibits B-Raf V600E mutant, was recently investigated in clinical trials [XREF_BIBR - XREF_BIBR]."

23617957

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"Dabrafenib is also an inhibitor of the V600E BRAF which, as mentioned above, plays a role in the regulation of cell growth [XREF_BIBR]."

24455677

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"BRAF V600E inhibitors including vemurafenib and dabrafenib show clinical responses in many cases of BRAF V600E mutated cancers."

26350141

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"Further, clinically approved B-Raf inhibitors, vemurafenib and dabrafenib inhibit the mutated B-Raf V600E enzyme, preventing MEK activation in patients with the mutation [74]."

29872754

Dabrafenib inhibits BRAF. 10 / 10

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"In addition, dabrafenib is a well-known inhibitor of B-Raf, which suppresses the downstream Ras/Raf/ERK/MAPK pathway, which has been approved for clinical use for the treatment of non small cell lung cancer expressing B-Raf V600E mutations and in melanoma."

32613000

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"Vemurafenib and dabrafenib are small molecule inhibitors of BRAF approved for use in patients with advanced melanoma harbouring a V600 BRAF mutation (NCCN Practice Guidelines in Oncology melanoma version 4.2014 [www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf])."

26059332

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"This has implications for combination treatment strategies in melanoma where BRAF and MEK kinase inhibitors such as dabrafenib and trametinib may make melanoma cells less permissive of TVEC viral replication and cellular lysis."

29420123

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"Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600 -mutated advanced melanoma."

30410366

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"Examples are imatinib, targeting a specific fusion protein of ABL kinase in chronic myeloid leukemia [XREF_BIBR], and vemurafenib and dabrafenib, targeting a mutant form of the protein kinase BRAF in metastatic melanoma [XREF_BIBR, XREF_BIBR]."

26018524

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"To report the diagnosis of acute VKH like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor)."

27892777

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"Selective BRAF inhibition by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. 44999999="V600"}"

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"XREF_BIBR In addition, trials studying the combination of BRAF and MEK inhibitors such as dabrafenib and trametinib (an MEK1 and MEK2 inhibitor) indicated improved survival, and currently ongoing trials are studying the combination with checkpoint inhibitors."

28224120

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"BRAF V600 inhibitors such as vemurafenib and dabrafenib leading to the activation, of several mechanisms of resistance [XREF_BIBR]."

26619946

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"In patients with BRAFV600E positive melanoma enrolled in large randomized phase III studies, treatment with BRAF kinase inhibitors such as vemurafenib and dabrafenib resulted in response rates of over 50-60% and progression-free survival (PFS) of 6-7 months."

26498143

Dabrafenib inhibits BRAF. 2 / 2

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No evidence text available

23237741

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No evidence text available

20823850

Dabrafenib inhibits BRAF-V600K. 1 / 1

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"Dabrafenib inhibits the mutant BRAF (BRAF (mut)) protein in melanomas with BRAF (V600E) and BRAF (V600K) genotypes."

23251089

Dabrafenib activates BRAF.

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Dabrafenib activates BRAF. 10 / 10

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"Since both extracranial metastases and BM also exhibit a broad response to vemurafenib, dabrafenib and other drugs targeting oncogenic BRAF [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."

30053879

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"Patients with ROS1 positive NSCLC are treated with crizotinib and those with BRAF V600 mutation positive advanced or metastatic NSCLC are treated with acombination of dabrafenib and trametinib."

29983826

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"There are three reports on pediatric patients with BRAF mutated brain tumors treated with dabrafenib."

29039591

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"Dabrafenib, which specifically targets and inhibits BRAF, similar to vemurafenib, may be associated with less cutaneous squamous cell carcinoma or keratoacanthoma than vemurafenib, although it is associated with more pyrexia."

26705496

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"Here, we report a complete response followed by clinical progression in a patient with a BRAF V600E-mutant brain tumor treated with dabrafenib."

29880583

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"Here we analyse 20 BRAF (V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response."

25452114

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"This PK profile of LY3009120 supports continued use of solid dispersion as the initial formulation for clinical development.Selective BRAF inhibitors vemurafenib and dabrafenib paradoxically activate downstream signaling, promote tumor growth in the WT BRAF cells, and are contraindicated for treatment of cancer patients whose tumors harbor a RAS mutation."

26343583

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"We analyzed 146 patients with BM from BRAF mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+ trametinib between 2010 and 2016."

29356790

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"However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors."

23844038

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"Data from four published datasets were analyzed to determine whether preexisting MEK1 (P124) mutations affect radiologic response or progression-free survival (PFS) in patients with BRAF (V600)-mutant metastatic melanoma treated with vemurafenib or dabrafenib."

25370473

Dabrafenib activates BRAF-V600E. 10 / 10

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"A total of 76 patients with BRAF V600E and 16 patients with V600K mutations were treated with dabrafenib 150 mg twice daily."

26767073

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"Improved survival in melanoma patients with BRAF V600E mutations treated with Vemurafenib and Dabrafenib shows promising results in the treatment of this devastating disease (Chapman et al., 2011; Hauschild et al., 2012)."

25236573

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"In our patient with an IDH wild-type epithelioid glioblastoma and a V600E mutation of the BRAF kinase treated with dabrafenib as salvage therapy, we achieved clinical and radiological stability over ten months, which is remarkable at that point of the clinical course with extensive pretreatment (XREF_FIG)."

29621181

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"Investigational nonchemotherapy options include moxetumomab pasudotox, which targets CD22; vemurafenib or dabrafenib, each of which targets the BRAF V600E protein; trametinib, which targets mitogen activated protein kinase enzyme (MEK); and ibrutinib, which targets Bruton tyrosine kinase (BTK)."

29742076

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"We report a case of a 35-year-old man with BRAF (V600E) metastatic melanoma treated with dabrafenib (as well as ipilimumab and whole brain radiotherapy), who is alive, 25 months after the onset of his DMC."

25159853

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"Interestingly, it was recently shown that the small molecule kinase inhibitor dabrafenib (Tafinlar) not only targets oncogenic mutant BRAF V600E but also potently inhibits CDK16 17 and that this mechanism may contribute to the efficacy of this drug against BRAF wild-type (WT) tumors 18."

30992425

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"In some studies, dabrafenib targeting of BRAF V600E decreased downstream phosphorylation of MEK and ERK [XREF_BIBR, XREF_BIBR]."

28131904

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"There is evidence regarding B-RAF inhibition activity in lung cancer, such as that reported in some case reports [XREF_BIBR, XREF_BIBR] and proved by interim analysis of a phase II trial, in which patients with BRAF V600E lung cancer beyond first line were treated with dabrafenib and obtained an ORR of 54% [XREF_BIBR]."

27433281

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"In a single case of BRAF V600E mutated NSCLC treated with dabrafenib, molecular profiling revealed three new acquired mutations in KRAS, TP53, and CDKN2A."

26301799

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"In this study, we report on the first case series of 3 patients with BRAF V600E mutated, malignant glioma and leptomeningeal disease successfully treated with dabrafenib."

29039591

Dabrafenib activates mutated BRAF. 10 / 10

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"We report a case of a patient with metastatic cutaneous BRAF mutant melanoma treated with dabrafenib who underwent repeat debulking surgery for a resistant lesion while disease in other metastatic sites was controlled."

24858661

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"Three (23%) were found positive for the presence of the BRAF mutation and were treated with the BRAF inhibitor dabrafenib."

26680369

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"Here, we show that when the human melanoma cell line A375SM (containing the active BRAF mutation) is treated with the BRAFi dabrafenib, P-ERK1/2 is significantly reduced, as expected, but Nodal expression is relatively unaffected (XREF_SUPPLEMENTARY)."

26460952

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"In response to the BRAF mutation, the patient was treated with dabrafenib (150mg) and trametinib (2mg) combination therapy in January 2018; after cycle 4 in April 2018, the CA-125 declined from 1186 to 102U/mL."

30246138

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"Dabrafenib and trametinib, used as single agents or in combination, have produced a significant improvement on the outcomes of patients with metastatic melanoma harboring BRAF mutations, and have changed the scope of treatment in this setting."

29384960

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"The immunomodulating CTLA-4 inhibitor ipilimumab is effective in some patients with asymptomatic and stable brain metastases, whilst the BRAF inhibitors vemurafenib and dabrafenib produce responses in BRAF mutant melanoma patients with symptomatic brain metastases."

27711083

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"Given the high response rate of BRAF V600E positive metastatic melanoma to mutant BRAF targeted inhibition by vemurafenib XREF_BIBR or dabrafenib XREF_BIBR, our observations also offer a rationale for future testing of BRAF targeted therapeutics for ameloblastoma."

24374844

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"Indeed, a second clinical grade RAF inhibitor, dabrafenib, effectively inhibits mutant BRAF signaling, elicits strong clinical responses in patients but also induces the formation of cuSCC/KA."

23490205

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"In a multicenter phase II trial, 172 patients with BRAF mutant melanoma with at least one asymptomatic brain metastasis were treated with dabrafenib."

28993799

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"An important approach to treatment for melanoma is the use of inhibitors such as vemurafenib, dabrafenib, or cobimetinib, which specifically target the mutant BRAF."

27583134

Dabrafenib activates BRAF-V600R. 2 / 2

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"The second patient had stage III BRAF V600R mutant melanoma that was treated with pembrolizumab and dabrafenib, and also developed a regressed melanocytic nevus."

29152725

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"Of note, a clinical report on patients with the BRAF V600R mutation who were treated with vemurafenib or dabrafenib has shown promise; however, the activity of BRAF inhibitors in other, more rare, BRAF mutations remains unknown."

25597784

Dabrafenib activates BRAF-V600K. 1 / 1

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"Unlike vemurafenib, which inhibits BRAF V600E and the RAF isoform CRAF with similar potency, dabrafenib is a more selective inhibitor of BRAF V600E and also targets the BRAF V600K mutant (lysine substitution for valine) that is detected in 7-20% of melanomas and causes activation of the MAPK pathway [43]."

24210882

Dabrafenib binds BRAF.

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Dabrafenib binds BRAF. 8 / 8

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"Dabrafenib bound to BRAF and ARAF with IC 50 of 6 and 26 nM, respectively, while its binding affinity to CRAF displayed an IC 50 of 150 nM, ~ 25-fold less than BRAF."

26343583

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"Comparison of the dabrafenib bound BRAF DeltaNVTAP and BRAF V600E structures reveals the overall kinase domain is largely unaffected (RMSD ~ 0.7 A), and the dimerization interface is preserved."

26996308

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"In contrast, as the dabrafenib binding mode requires the alphaC out conformation, dabrafenib binding to BRAF DeltaNVTAP results in significant local perturbation to the beta3-alphaC loop and alphaC."

26996308

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"For this purpose, we explored the interaction between dabrafenib and B-Raf."

24901049

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"A similar pattern of collective motions could be seen the BRAF and Dabrafenib complex (XREF_FIG)."

27861609

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"The most probable path in the Dabrafenib and BRAF complex (85% occupancy) could proceed from F595 of monomer A to the R-spine residues of the alphaC-helix (V504, L505), subsequently reaching to the interfacial residue R509 of the monomer A (XREF_FIG)."

27861609

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"The relatively high B factors for alphaC in all four copies of dabrafenib bound BRAF DeltaNVTAP in the asymmetric unit suggest that this region is less ordered than in the AZ-628- or sorafenib-BRAF DeltaNVTAP, or BRAF WT structures."

26996308

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"The small molecule inhibitors vemurafenib and dabrafenib selectively bind the active conformation of BRAF and inhibit signal transduction between BRAF and MEK."

26174532

Dabrafenib affects ERK

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Dabrafenib inhibits ERK.

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Dabrafenib inhibits ERK. 10 / 10

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"More recently, it has been shown that the combination of dabrafenib and trametinib treatment decreased ERK activation, cell proliferation and induced apoptosis in human cancer cell lines harboring non V600 BRAF mutations, which accounts for approximately half of BRAF mutated NSCLC [XREF_BIBR]."

29455659

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"However, the triple combination dabrafenib, trametinib, and SHP099 markedly suppressed p (Y542) SHP2 (XREF_FIG) and ERK signaling (XREF_FIG) and growth (XREF_FIG) of RKO xenograft tumors, without any obvious effect on body weight (XREF_SUPPLEMENTARY), providing further evidence that combined ERK signaling and SHP2 inhibition may be an effective therapeutic strategy for patients with BRAF (V600E) colorectal tumors."

30605687

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"Thirty-fold higher concentrations of dabrafenib were required to inhibit ERK signaling in the latter compared with the former."

26343582

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"CRAF expression reduced Dabrafenib mediated ERK inhibition, but barely altered AZ628 mediated ERK inhibition."

29662630

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"A clinically relevant dose of Dabrafenib, a type I RAF-inhibitor, in HEK293T cells reduced ERK activity induced by BRAF mutations conferring high kinase activity in the presence and absence of CRAF."

28947956

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"Dabrafenib, an inhibitor of RAF-1 and B-RAF, suppressed the early activation of ERK, but a significant amount of phosphorylated ERK remained after 60min of shaking in the presence of dabrafenib (XREF_FIG A), which gradually increased over time only when FSS was applied (XREF_FIG C)."

28956013

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"Although both trametinib and dabrafenib blocked ERK1/2 activation in resistant cells, neither RAF and MEK inhibitor was able to effectively block cell proliferation, suggesting that the resistant cells were no longer RAF and MEK dependent."

29296217

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"Inhibitory effect of Dabrafenib on mutant BRAF induced ERK signaling."

28947956

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"Combination of Dabrafenib and Trametinib enhances and prolongs ERK inhibition in non V600 BRAF mutated cell lines."

28947956

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"30-fold higher concentrations of dabrafenib were required to inhibit ERK signaling in the latter compared to the former (XREF_FIG)."

26343582

Dabrafenib inhibits phosphorylated ERK. 4 / 4

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"Moreover, dabrafenib increased p-C-Raf and decreased p-MEK1/2 and p-ERK in both cell lines (XREF_FIG)."

26630652

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"In CRMM1, the lowest dose of Vemurafenib (0.4 muM) and Dabrafenib (0.005 muM) already inhibited p-ERK."

28938534

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"Importantly, TAS-116 and dabrafenib synergistically inhibited p-MEK1/2 and p-ERK (XREF_FIG)."

26630652

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"In contrast, in CM2005.1, increasing dosages of Vemurafenib and Dabrafenib decreased p-ERK gradually, while total ERK levels were not suppressed."

28938534

Dabrafenib activates ERK.

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Dabrafenib activates ERK. 10 / 10

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"To further investigate the capacity of Dabrafenib and AZ628 to induce paradoxical ERK activation, we compared ERK activation between WT BRAF expressing, CRAF expressing, and WT BRAF and CRAF co-expressing HEK293T cells following 2 h AZ628 treatment."

29662630

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"To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation."

27028853

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"In contrast, dabrafenib did not increase basal activity of MEK and ERK and efficiently suppressed light dependent activation of BRAF."

27025703

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"In addition, progression of a previously present KRAS mutated colon carcinoma due to stimulated ERK signaling was reported in a patient with a melanoma treated with dabrafenib [XREF_BIBR]."

26786320

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"In fact, both vemurafenib and dabrafenib actually increase MEK and ERK activation in the setting of RAS mutations."

23438383

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"In cells transfected with CRAF alone, Dabrafenib, but not AZ628, induced paradoxical ERK activation."

29662630

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"As before, dabrafenib and encorafenib stimulated ERK at lower levels,, at 3.90 +/- 0.34 and 4.04 +/- 0.16 fold above control, respectively."

27028853

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"As before, dabrafenib and encorafenib stimulated ERK at lower levels, (Figure - ), at 3.90 ± 0.34 and 4.04 ± 0.16 fold above control, respectively (Figure - , Table )."

27028853

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"Conversely, in KRAS-mut contexts (MiaPaCa2 pancreatic cancer; A549 and A-427 NSCLC), EGFR family activation was dispensable for dabrafenib induced paradoxical ERK activation, as the addition of lapatinib to dabrafenib had no appreciable effect on ERK activation."

29986755

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"Dabrafenib induced significant phospho-MEK and -ERK activation at concentrations up to 1 muM and inhibited the phospho-MEK and -ERK at a high concentration of 10 muM."

26343583

Dabrafenib activates phosphorylated ERK. 4 / 4

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"Furthermore, to verify if MMP-9 may be involved in the mechanism of resistance to BRAF inhibitors A375 resistant cells were obtained and pERK protein levels showed opposite behavior compared to sensitive cells when treated with dabrafenib."

30154717

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"Although others have previously shown that RAF inhibitors paradoxically activate ERK signaling in wild-type BRAF and RAS mutated tumors [XREF_BIBR, XREF_BIBR - XREF_BIBR], we here confirmed that dabrafenib (1.25 to 2.5 muM) activated p-MEK1/2 and p-ERK in both cell lines, suggesting that paradoxical activation also occurs in MM (XREF_SUPPLEMENTARY)."

26630652

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"The pERK rebound was also elicited by dabrafenib, a more potent RAF inhibitor (XREF_SUPPLEMENTARY)."

23153539

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"Importantly, TAS-116 enhanced the inhibition of p-MEK1/2 or p-ERK induced by dabrafenib."

26630652

Dabrafenib phosphorylates ERK.

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Dabrafenib leads to the phosphorylation of ERK. 4 / 4

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"The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells."

30262568

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"Furthermore, MEK1 (P124Q/S) mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1."

25370473

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"In HEK293T cells co-expressing WT BRAF and CRAF, Dabrafenib increased ERK phosphorylation (p-ERK) at all tested concentrations (8, 80, and 800 nM)."

29662630

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"In this case, dabrafenib did not inhibit but increased basal phosphorylation of MEK and ERK and further increased CRAF signaling induced by light exposure (XREF_FIG)."

27025703

Dabrafenib increases the amount of ERK.

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Dabrafenib increases the amount of phosphorylated ERK. 4 / 4

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"In D594N BRAF and CRAF co-expressing HEK293T cells, both Dabrafenib and AZ628 treatment slightly increased p-ERK levels at 8 and 80 nM, and downregulated p-ERK at 800 nM."

29662630

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"Dabrafenib enhanced pERK expression levels and did not suppress human CD4 (+) or CD8 (+) T-cell function."

25589619

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"At low concentration ranges between 50nM and 1000nM, dabrafenib increased p-ERK1/2 levels accompanied with elevation of DR5 in three representative Ras-mutant cell lines (XREF_FIG)."

27222248

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"The model was an extension of the model of PC-12 (rat adrenal gland) cells [XREF_BIBR] and showed that increasing dabrafenib concentrations cause declining pERK levels but in unphysiological ranges."

32410672

Dabrafenib dephosphorylates ERK.

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Dabrafenib leads to the dephosphorylation of ERK. 4 / 4

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"Furthermore, our western blot analysis shows that phosphorylation of ERK, a major downstream target of BRAF, is inhibited in these cells by dabrafenib."

29039591

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"XREF_BIBR In vitro models have demonstrated that dabrafenib significantly decreases ERK phosphorylation, resulting in cell arrest in G1 phase and subsequent cell death."

29662327

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"18Both dabrafenib and trametinib inhibit ERK and MEK phosphorylation in other models of BRAF mutation positive melanoma."

25797743

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"45 Our results showed that vemurafenib and dabrafenib were not able to decrease levels of ERK phosphorylation significantly in mutated cases, although a slight effect was observed after dabrafenib treatment which could be an off-target effect."

30262568

Dabrafenib decreases the amount of ERK.

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Dabrafenib decreases the amount of phosphorylated ERK. 1 / 1

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"As expected, Dabrafenib treatment of HEK293T cells singly expressing BRAF mutants with elevated kinase activity led to decreased p-ERK1/2 levels."

28947956

Dabrafenib affects MAPK

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Dabrafenib inhibits MAPK.

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Dabrafenib inhibits MAPK. 10 / 10

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"Dabrafenib is a reversible, ATP-competitive inhibitor that selectively inhibits BRAF V600E kinase; preclinical data indicate that dabrafenib inhibits the MAPK pathway in BRAF V600E mutated melanoma cells, leading to decreased proliferation and regression in xenograft models."

24971404

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"The MAPK pathway was inhibited by the BRAF inhibitor dabrafenib and the PI3K-AKT pathway was inhibited by the AKT inhibitor GSK2141795B (AKTi)."

24735930

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"Intraperitoneal daily delivery of BRAF V600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341 luc tumor."

27713119

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"Both Dabrafenib and Trametinib inhibit the MAPK pathway and are applied in the treatment of metastatic cutaneous melanoma."

28818062

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"In this paper, we use time-lapse, live-cell imaging, and single-cell analysis to show that BRAF-mutant melanoma cells exhibit time-variable and heterogeneous phenotypes when exposed to MAPK pathway inhibitors such as vemurafenib, dabrafenib, and trametinib near the IC 50 for cell killing."

28069687

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"MAPK pathway inhibitors -- including the RAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib -- achieve clinicalbenefit in 80-90% ofBRAF V600 -mutant melanoma patients."

24771846

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"The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen activated protein kinase (MAPK) pathway for melanoma treatment."

30444343

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reach

"It is clear that the subset of melanoma patients with activating mutations in BRAF derive the most benefit from MAPK pathway inhibitors such as vemurafenib, dabrafenib, and trametinib, but individual patient responses are variable and, more importantly, transient due to the rapid development of resistance."

23285177

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reach

"Like vemurafenib, dabrafenib downregulates activation of MAPK signaling."

28131904

➶

reach

"Subsequent studies have demonstrated that the approved doses of both vemurafenib and dabrafenib produce a marked (> 90%) inhibition of MAPK pathway activation in biopsies of non CNS metastases."

27615400

Dabrafenib activates MAPK.

| 9

Dabrafenib activates MAPK. 9 / 9

| 9

➶

reach

"XREF_BIBR Surprisingly, the incidence of cutaneous squamous cell carcinoma was decreased on combination therapy compared with monotherapy using dabrafenib (7% versus 19%), possibly because MEK inhibition by trametinib attenuates dabrafenib induced paradoxical activation of the MAPK pathway in normal keratinocytes."

24516336

➶

reach

"In light of the evidence that BRAF and MEK inhibitors have different effects on the MAPK pathway in BRAF wild-type cells, XREF_BIBR - XREF_BIBR it appears likely that trametinib attenuates dabrafenib induced activation of the MAPK pathway."

23020132

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reach

"Examining our immunoblotting, cell cycle, and mutational profiling data collectively, we hypothesize that nucleotide pool depletion by competing cell signals of MTX induced ssDNA damage repair and dabrafenib induced MAPK pathway activation ultimately triggers cell death in BRAFi resistant MM cells."

29568360

➶

reach

"Treatment with 10muM dabrafenib for two hours did not significantly increase CRAF and CRAF-CIBN expression but still led to slightly elevated MEK and ERK phosphorylation, indicating that the MAPK cascade activation by dabrafenib is not solely attributable to the CRAF protein level (XREF_FIG)."

27025703

➶

reach

"In these contexts, MAPK activation was found to be dependent on EGFR family activation : indeed, the EGFR and HER2 inhibitor lapatinib strongly reduced dabrafenib induced MAPK activation."

29986755

➶

reach

"Dabrafenib activates the MAPK pathway and disrupts MTX induced single-strand DNA damage repair causing apoptosis in acquired resistant MM cells."

29568360

➶

reach

23844038

➶

reach

"Herein, we will focus on 4 recently published NEJM papers reporting the results of clinical trials, comprising 4 agents targeting the MAPK pathway : the BRAF inhibitors vemurafenib and dabrafenib, and the MEK inhibitors trametinib and cobimetenib."

26016850

➶

reach

"We postulate that nucleotide pool depletion and ssDNA break induction by MTX may disrupt downstream transcriptional reprogramming activated by the dabrafenib induced MAPK pathway ultimately triggering cell death."

29568360

Y-27632 affects ROCK1

8 1 | 2 8

Y-27632 inhibits ROCK1. 10 / 10

8 | 2

➶

tas

No evidence text available

25248678

➶

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No evidence text available

➶

tas

No evidence text available

23275831

➶

tas

No evidence text available

18077363

➶

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No evidence text available

26356532

➶

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No evidence text available

20000469

➶

eidos

"19 In vitro inhibition of ROCK1 by Y27632 leads to a reduction in the number of podosomes , reduced motility and phagocytosis , and an increased matrix degradation.18 ,20 RhoA also plays a role in the accumulation of macrophages in blood vessels ."

32548242

➶

eidos

"The RhoA / Rho-kinase ( ROCK ) pathway is a key regulator of vascular function in health and disease.34 To understand if the impaired endothelial function was mediated by activation of ROCK signaling , we assessed endothelium-dependent relaxation in carotid arteries from male and female offspring in response to Y-27632 , which inhibits both ROCK1 and ROCK2 equally ."

31104564

➶

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No evidence text available

16249185

➶

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No evidence text available

21145740

Y-27632 inhibits ROCK1. 8 / 8

| 8

➶

medscan

"Inhibition of ROCK1 and ROCK2 by Y-27632 significantly inhibits proliferation, migration, and invasion of laryngeal squamous cell carcinoma cells."

25755711

➶

medscan

"This functional desensitization was blocked by the Rho kinase (ROCK) inhibitor, Y-27632, but not by Gq or Gs-pathway inhibitors or inhibition of β-arrestin recruitment."

28619258

➶

medscan

"Y-27632, which selectively inhibits p160ROCK [ ], 3-Methyladenine, Bafilomycin A1, and Z-VAD-FMK were obtained from Calbiochem (San Diego, CA, USA)."

25944062

➶

medscan

"Both a Rho inhibitor C3 exoenzyme and a Rho kinase (ROCK) inhibitor Y-27632 inhibited chemotaxis of rat basophilic leukemia-2H3 cells expressing human CCR1 cells toward CCL3, indicating that activation of the Rho/ROCK signaling pathway is required for the CCL3-mediated chemotaxis of the cells."

15337751

➶

medscan

"Treatment with the Rho kinase (ROCK) inhibitor Y-27632 caused a decrease in human microlymphatic endothelial cells of dermal origin barrier function."

21417762

➶

medscan

"Suppression of RhoA and Rho-kinase activities by anti-RhoA immunoglobulin G electroporation and Y-27632, respectively prevented morphologic changes and restored plasma membrane localization of occludin."

23963366

➶

medscan

"We also found that the inhibition of ROCK1 by Y-27632 can inhibit the invasion and migration of gastric cells done at least, in part, by attenuating SRF expression."

23134219

➶

medscan

"The objective of this study is to determine the effects of Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor Y-27632 on the growth, invasion, and migration of Tca8113 and CAL-27 cells in tongue squamous cell carcinoma ."

26468018

Y-27632 inhibits ROCK1. 1 / 1

1 |

➶

drugbank

No evidence text available

10592235

Dabrafenib affects MPRIP

| 3 14

Dabrafenib inhibits MPRIP.

| 10

Dabrafenib inhibits MPRIP. 9 / 9

| 9

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reach

"29 Dabrafenib inhibited RIP3 also 27-fold more potently than vemurafenib as determined by the luminescent assay (XREF_TABLE)."

24901049

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reach

"Dabrafenib inhibits RIP3 independently of its effect on the B-Raf family members."

24901049

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reach

"28 These data collectively indicate that (1) both RIP3 inhibition and B-Raf V600E inhibition are separable, (2) the biological outcomes of their inhibition are mutually independent and (3) dabrafenib inhibits RIP3 independently of its effect on the B-Raf family members."

24901049

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reach

"On the other hand, only dabrafenib reversed TSZ induced necroptosis in RIP3 expressed HT29 cells, possibly because the other 2 B-Raf V600E inhibitors have significantly weak RIP3 inhibitory activity (XREF_TABLE)."

24901049

➶

reach

"The B-Raf V600E inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen induced liver injury."

24901049

➶

reach

"Moreover, our data showed that dabrafenib inhibited RIP3 independently of its effect on the B-Raf family members."

24901049

➶

reach

"The B-Raf inhibitor dabrafenib selectively inhibits RIP3 kinase activity by its ATP-competitive binding to the enzyme protein."

24901049

➶

reach

"Selectivity analyses against the RIP family members revealed that dabrafenib inhibited RIP3 26600-, 38- and 14675-fold more potently than RIP1, RIP2 and RIP5, respectively (XREF_FIG)."

24901049

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reach

"The human RIP3 inhibition by dabrafenib achieved similar effects to RIP3 deficiency in preventing acetaminophen induced hepatocyte necrosis 17 and ethanol caused liver injury 8 in mice."

24901049

Dabrafenib bound to ATP inhibits MPRIP. 1 / 1

| 1

➶

reach

"By competitively binding of ATP to the enzyme protein dabrafenib inhibited RIP3 with high selectivity relative to other RIP family members."

24901049

Dabrafenib binds MPRIP.

| 3 4

Dabrafenib binds MPRIP. 7 / 7

| 3 4

➶

reach

"We next investigated the possibility of the direct interaction between dabrafenib and RIP3."

24901049

➶

reach

"For the docking study on the binding of dabrafenib to RIP3, we performed the homology modeling of human RIP3 based on the B-Raf crystal structure 3SKC."

24901049

➶

medscan

"For the docking study on the binding of dabrafenib to RIP3, we performed the homology modeling of human RIP3 based on the B-Raf crystal structure 3SKC."

24901049

➶

reach

"The data suggest that dabrafenib could directly bind to RIP3."

24901049

➶

medscan

"The data suggest that dabrafenib could directly bind to RIP3."

24901049

➶

reach

"Dabrafenib did not bind to the GST tag in the recombinant RIP3 protein (XREF_FIG, upper panel), excluding its influence on the assay for the binding of dabrafenib to RIP3."

24901049

➶

medscan

"Dabrafenib did not bind to the glutathione S-transferase tag in the recombinant RIP3 protein ( , upper panel), excluding its influence on the assay for the binding of dabrafenib to RIP3."

24901049

Dabrafenib affects vemurafenib

| 16

Dabrafenib activates vemurafenib.

| 10

Dabrafenib activates vemurafenib. 10 / 10

| 10

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reach

"XREF_BIBR Keratic lesions occur in 12% patients treated with vemurafenib and in 8% treated with dabrafenib."

30038659

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reach

"This is consistent with the slightly higher objective intracranial response rate seen in the phase II MBM study with dabrafenib compared to the phase II MBM study with vemurafenib, where the patient population treated with dabrafenib had fewer patients with> 4BMs (21% vs. 33%) XREF_BIBR, XREF_BIBR."

25991583

➶

reach

"Photosensitivity sunburn is commonly seen in patients treated with vemurafenib but has not been reported in patients treated with dabrafenib."

25467940

➶

reach

"For example, photosensitivity is common in patients treated with vemurafenib and much less frequent in patients treated with dabrafenib, whereas fever and chills are much more frequent with dabrafenib treatment."

27226731

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reach

"Arthralgias are more common in patients treated with vemurafenib than in patients treated with dabrafenib; in 1 trial of vemurafenib, 53% of treatment-naive melanoma patients had arthralgias 76, and in 1 trial of dabrafenib, 27% of patients had arthralgias 120."

25467940

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reach

"Sixty-seven patients were treated with vemurafenib, and 11 patients were treated with dabrafenib."

30096703

➶

reach

"Patients treated with vemurafenib developed a cuSCC more quickly than those treated with dabrafenib (P =.048) (Fig 1, C)."

25748298

➶

reach

"It has been observed in 6-19% XREF_BIBR, XREF_BIBR of patients treated with vemurafenib and 13% 44 of patients treated with dabrafenib."

25467940

➶

reach

"SCCs and keratoacanthomas were detected in approximately 20-30% of patients in the trials of vemurafenib, and approximately 10% of patients treated with dabrafenib [XREF_BIBR, XREF_BIBR]."

26594316

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reach

"Among the 22 patients, 11 were subjected to dabrafenib or vemurafenib monotherapy, whereas 3 were treated with dabrafenib alone for 8, 5 or 4 months and then with dabrafenib plus trametinib."

29371923

Dabrafenib binds vemurafenib.

| 4

Vemurafenib binds dabrafenib. 4 / 4

| 4

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reach

"After four cycles of carboplatin and pemetrexed the CT showed no response, switch to docetaxel is planned at the time of the writing of this report.We computed a 3-dimensional structure model of BRAF G469L, which suggested impaired binding of vemurafenib and dabrafenib, providing a theoretical explanation for the clinical course of our patient."

24035431

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reach

"Both vemurafenib and dabrafenib inhibit mutant BRAF by binding to the ATP binding pocket that in the setting of mutant BRAF monomers potently inhibit RAF/MEK/ERK signaling."

26236691

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reach

"In preclinical studies, there is strong evidence for the interaction of vemurafenib, dabrafenib, trametinib, palbociclib, cobimetinib and omipalisib with P-gp and BCRP."

28546917

➶

reach

"Three-dimension structural modeling of BRAF G469L suggested that it induces a conformational change impairing the binding of vemurafenib and dabrafenib."

26301799

Dabrafenib inhibits vemurafenib.

| 2

Dabrafenib inhibits vemurafenib. 2 / 2

| 2

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reach

"Reduction in circulating tumor DNA (ctDNA) BRAF level is associated with tumor regression by RECIST : maximum ctDNA BRAFV600 level reduction occurs in Cycle 2 and 3 time points in vemurafenib treated patients and in at least Cycle 4 in patients treated with the combination of dabrafenib and trametinib."

29145885

➶

reach

"For most BRAF mutated melanoma patients and particularly those with a high tumor load, vemurafenib or other BRAF inhibitors such as dabrafenib are the treatment of choice."

24413374

Sotrastaurin affects apoptotic process

| 1 13

Sotrastaurin activates apoptotic process.

| 10

Sotrastaurin activates apoptotic process. 10 / 10

| 10

➶

reach

"et al found that AEB071 at high doses (5muM) induced apoptosis in 92-1, mel202 and omm1.3 uveal melanoma cell lines, which harbor GNAQ mutations."

24141786

➶

reach

"These results indicate that AEB071 selectively induced apoptosis in UM cells harboring GNAQ mutations."

22653968

➶

reach

"AEB071 induced apoptosis is associated with decreased expression of antiapoptotic proteins, yet the underlying molecular mechanisms remain to be revealed."

22653968

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reach

"The combination of AEB071 and the PI3Kalpha inhibitor BYL719 synergistically inhibited proliferation and induced apoptosis in GNAQ- and GNA11-mutant cell lines 102 and is being investigated in a phase Ib trial in metastatic uveal melanoma [ClinicalTrials.gov identifier : NCT02273219]."

29497459

➶

reach

"Furthermore, we demonstrated that the PKC inhibitor sotrastaurin induced cell apoptosis and cell cycle arrest in DLBCL cells potentially through regulating the expression of MCT-1."

29534146

➶

reach

"We next examined whether AEB071 promoted apoptosis in UM cells."

22653968

➶

reach

"AEB071 and BYL719 combination induces apoptosis."

24563540

➶

reach

"Unlike former PKC inhibitors, AEB071 did not enhance apoptosis of murine T-cell blasts in a model of activation induced cell death."

19491325

➶

reach

"Interestingly, targeting PKC and BTK at the same time led to ibrutinib mediated rescue of a weak sotrastaurin induced apoptosis in MINO cells."

26914495

➶

reach

"This is important since higher concentrations of AEB071 are known to cause cell cycle perturbations and apoptosis in certain cell types."

26420215

Sotrastaurin inhibits apoptotic process.

| 1 3

Sotrastaurin inhibits apoptotic process. 4 / 4

| 1 3

➶

reach

"A selective PKC inhibitor, sotrastaurin, effectively inhibited cell proliferation and induced cell apoptosis in a dose- and time dependent manner."

29534146

➶

reach

"Finally, neither NAC nor AEB071 inhibited cellular apoptosis maximally."

28548942

➶

sparser

"Finally, neither NAC nor AEB071 inhibited cellular apoptosis maximally (Figure xref )."

28548942

➶

reach

"Expression of PIM-1L-wildtype or -S65D reduced sotrastaurin mediated apoptosis and growth inhibition in MV4-11 transfectants."

30017192

Y-27632 affects ROCK2

9 1 | 1 2 1

Y-27632 inhibits ROCK2.

9 1 | 1 2

Y-27632 inhibits ROCK2. 10 / 10

9 | 1

➶

tas

No evidence text available

21145740

➶

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No evidence text available

➶

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No evidence text available

12672248

➶

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No evidence text available

25248678

➶

eidos

31104564

➶

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No evidence text available

20000469

➶

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No evidence text available

20462760

➶

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No evidence text available

23275831

➶

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No evidence text available

26356532

➶

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No evidence text available

24119557

Y-27632 inhibits ROCK2. 2 / 2

| 2

➶

medscan

"Furthermore, Y-27632, an inhibitor of ROCK2, attenuated the Angiotensin II-induced contraction of human airway smooth muscle cells by blocking the RhoA/ROCK2 signaling pathway which is involved in this contraction, and thus may be a major regulator involved in the basal maintenance of contractility in human airway smooth muscle cells."

22842919

➶

medscan

"Inhibition of ROCK1 and ROCK2 by Y-27632 significantly inhibits proliferation, migration, and invasion of laryngeal squamous cell carcinoma cells."

25755711

Y-27632 inhibits ROCK2. 1 / 1

1 |

➶

drugbank

No evidence text available

10592235

Y-27632 activates ROCK2.

| 1

Y-27632 activates ROCK2. 1 / 1

| 1

➶

reach

"Furthermore, Y-27632, an inhibitor of ROCK2, attenuated the Ang II-induced contraction of HASMCs by blocking the RhoA/ROCK2 signaling pathway which is involved in this contraction, and thus may be a major regulator involved in the basal maintenance of contractility in HASMCs."

22842919

Dabrafenib affects RAF1

1 | 13

Dabrafenib inhibits RAF1.

1 | 6

Dabrafenib inhibits RAF1. 7 / 7

1 | 6

➶

reach

"XREF_BIBR At higher concentrations, dabrafenib also inhibits wild-type BRAF and CRAF kinases and other kinases such as salt inducible kinase 1 (SIK1), NIMA related kinase 11 (NEK11), and LIM domain kinase 1 (LIMK1)."

25506209

➶

reach

"Dabrafenib also inhibits wild type BRAF and CRAF kinases."

30881466

➶

tas

No evidence text available

➶

reach

"The IC50 of Dabrafenib to inhibit CRAF is ~ 10-fold less than that of Vemurafenib [XREF_BIBR - XREF_BIBR]."

28947956

➶

reach

"Therefore it is likely that dabrafenib, at high concentration ranges, inhibits c-Raf, resulting in blockage of c-Raf-dependent ERK activation and subsequent DR5 upregulation."

27222248

➶

reach

"At higher concentrations dabrafenib inhibited CRAF signaling."

27025703

➶

reach

"Dabrafenib enhanced activity of light stimulated CRAF at low dose and inhibited CRAF signaling at high dose."

27025703

Dabrafenib activates RAF1.

| 4

Dabrafenib activates phosphorylated RAF1. 3 / 3

| 3

➶

reach

"Western blot analysis showed that TAS-116 markedly inhibited p-C-Raf, which was paradoxically activated by dabrafenib in U266 MM cells (XREF_FIG)."

26630652

➶

reach

"Moreover, dabrafenib increased p-C-Raf and decreased p-MEK1/2 and p-ERK in both cell lines (XREF_FIG)."

26630652

➶

reach

"Moreover, TAS-116 markedly inhibited p-C-Raf or p-Akt, which were paradoxically activated by dabrafenib in the U266 MM cell line."

26630652

Dabrafenib activates RAF1. 1 / 1

| 1

➶

reach

"Dabrafenib enhanced activity of light stimulated CRAF at low dose and inhibited CRAF signaling at high dose."

27025703

Dabrafenib phosphorylates RAF1.

| 2

Dabrafenib leads to the phosphorylation of RAF1 on S338. 2 / 2

| 2

➶

reach

"We observed that Dabrafenib treatment of all HEK293T transfectants resulted in phosphorylation of the transfected CRAF molecule at S338, irrespective of the presence and type of BRAF molecule."

28947956

➶

reach

"As expected, Dabrafenib treatment increased CRAF S338 phosphorylation, while AZ628 treatment only slightly elevated CRAF S338 phosphorylation."

29662630

Dabrafenib increases the amount of RAF1.

| 1

Dabrafenib increases the amount of RAF1. 1 / 1

| 1

➶

reach

"Already at a concentration of 1muM, dabrafenib elevated the protein level of the light-insensitive constructs CRAF and CRAF-CIBN, higher concentrations tested up to 10muM further increased their protein level (XREF_FIG)."

27025703

Dabrafenib affects trametinib

| 13

Dabrafenib activates trametinib.

| 8

Dabrafenib activates trametinib. 8 / 8

| 8

➶

reach

"XREF_BIBR Preliminary findings from another trial that combined dabrafenib and trametinib versus dabrafenib with ipilimumab found that several patients treated with the combination of dabrafenib and trametinib with ipilimumab had an increased incidence of colonic perforation."

27382311

➶

reach

"5-7 Two additional agents, the BRAF inhibitor dabrafenib and the mitogen activated protein kinase inhibitor trametinib have recently been approved (both in the USA, and dabrafenib in the European Union)."

24582505

➶

reach

"Median PFS was improved by 3.6 months in patients receiving dabrafenib concurrently with a 2 mg/day dose of trametinib when compared to patients only being treated with dabrafenib."

24108405

➶

reach

"Five patients received two different targeted regimens, including four patients treated with vemurafenib followed by dabrafenib plus trametinib, and one patient treated with dabrafenib followed by dabrafenib plus trametinib."

32411601

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reach

"Of note, the duration of the interval between first BRAFi and rechallenge in the 3 patients who achieved CR from the rechallenge spanned from 5.9 months (a patient who had first-line dabrafenib) to 20.8 months (a patient who had first-line dabrafenib plus trametinib), while in patients who had PD as rechallenge best response the interval of BRAFi drugs was from 0.9 (dabrafenib plus trametinib as first BRAFi) to 24.6 months (a patient treated with dabrafenib as first BRAFi)."

29360604

➶

| 7

Sotrastaurin inhibits GNAQ. 5 / 5

| 5

➶

reach

"These findings together suggest that AEB071 suppressed growth of GNAQ mutated UM cells via inhibition of multiple PKC isoforms."

22653968

➶

reach

"AEB071 inhibits cell proliferation in GNAQ and GNA11-mutant Uveal Melanoma cell lines with inhibition of the PKC/ERK1/2 pathway."

24563540

➶

reach

"AEB071 at low micromolar concentrations significantly decreased viability of all three GNAQ mutated cell lines (XREF_FIG)."

22653968

➶

reach

"The PKC inhibitors AEB071 and AHT956 selectively inhibit the growth of GNAQ or GNA11 mutant melanoma cell lines."

24141786

➶

reach

"In the present study we describe the first small molecule inhibitor that selectively exhibits antiproliferative activity of UM cells harboring GNAQ mutations : the novel PKC inhibitor AEB071 reduced viability of GNAQ mutated UM cell lines, but had little effect on those carrying wild type GNAQ."

22653968

Sotrastaurin inhibits mutated GNAQ. 2 / 2

| 2

➶

reach

"These findings together indicate that AEB071 selectively inhibited NF-kappaB activation in UM cells harboring GNAQ mutations."

22653968

➶

reach

"Importantly, we demonstrate that AEB071 selectively repressed NF-kappaB activation in UM cells harboring GNAQ mutations and this is accompanied by downregulation of multiple PKC isoforms, in particular PKCalpha, PKCdelta, and PKCepsilon."

22653968

Sotrastaurin activates GNAQ.

| 6

Sotrastaurin activates GNAQ. 3 / 3

| 3

➶

reach

"Treatment with 2 and 5 muM AEB071 for 72 hours significantly increased Annexin V positive (apoptotic) populations in GNAQ mutated 92.1 and Omm1.3 cells (XREF_FIG)."

22653968

➶

reach

"In contrast, AEB071 did not increase Annexin V positive cell populations or caspase-3 cleavage in UM cells harboring wild type GNAQ (XREF_FIG)."

22653968

➶

reach

"To test this hypothesis, UM cells carrying wild type GNAQ or GNAQ mutated at codon 209 were treated with the PKC inhibitor AEB071 (sotrastaurin), a PKC inhibitor that has potent activity against classical and novel PKC isotypes."

22653968

Sotrastaurin activates mutated GNAQ. 3 / 3

| 3

➶

reach

"These results indicate that AEB071 selectively induced apoptosis in UM cells harboring GNAQ mutations."

22653968

➶

reach

"To test this hypothesis, uveal melanoma cells harboring wild-type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus expressing short hairpin RNAs (shRNA) targeting PKC isoforms."

22653968

➶

reach

"To test this hypothesis, UM cells harboring wild type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus expressing shRNAs targeting PKC isoforms."

22653968

Dabrafenib affects apoptotic process

| 1 1 10

Dabrafenib activates apoptotic process.

| 1 1 8

Dabrafenib activates apoptotic process. 10 / 10

| 1 1 8

➶

reach

"Vemurafenib, encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines; however, a residual population of tumor cells survive."

32629178

➶

reach

"Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E."

32561648

➶

eidos

"Vemurafenib , encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines ; however , a residual population of tumor cells survive ."

32629178

➶

reach

"In COLO205 cells, SHR8443, trametinib and dabrafenib individually induced apoptosis, and the combination of SHR8443 and trametinib and dabrafenib showed enhanced apoptosis induction."

29296217

➶

reach

"We show that TAS-116 induced synergistic anti-MM cytotoxicity and enhanced dabrafenib induced apoptosis in RAS mutated MM cell lines."

26630652

➶

reach

"Although SHR8443 alone did not induce noticeable apoptosis in A375 cells, it enhanced the apoptosis induced by trametinib or dabrafenib."

29296217

➶

reach

"In addition, annexin V/PI staining showed that TAS-116 significantly enhanced apoptosis induced by dabrafenib in the U266 MM cell line (P < 0.001 in the combination treatment versus TAS-116 monotherapy; P < 0.01 in the combination treatment versus dabrafenib monotherapy) (XREF_FIG)."

26630652

➶

reach

"Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA."

25589619

➶

reach

"The combined administration of a SAMMSON specific ASO and dabrafenib, a BRAF inhibitor, induced apoptosis in the PDTX model, whereas administration of dabrafenib alone only inhibited tumor growth."

28415644

➶

medscan

"Combined treatment with dabrafenib and AKTi increases the subG1 fraction and induces apoptosis in cell lines sensitive to AKTi as single agent."

24735930

Dabrafenib inhibits apoptotic process.

| 2

Dabrafenib inhibits apoptotic process. 2 / 2

| 2

➶

reach

"We have shown that at clinically relevant doses, vemurafenib, but not dabrafenib, potently inhibits JNK signaling and suppresses apoptosis, which cooperates with paradoxical ERK activation to induce tumors [XREF_BIBR]."

27028853

➶

reach

29455659

Y-27632 affects ROCK

| 3 2 6 1

Y-27632 inhibits ROCK. 7 / 7

| 1 6

➶

medscan

"To investigate the effects of the Rho-dependent protein kinase (ROCK) inhibitor Y-27632 on the kinetics of E-cadherin, F-actin, and Oct3/4 distributions in dissociated human embryonic stem cells and to analyze their interactions morphologically, Y-27632-treated [R(i) (+)] and untreated [R(i) (-)] cells were immunohistochemically stained for E-cadherin and Oct3/4 within 24h of dissociation and also for F-actin."

22727933

➶

medscan

"Rho kinase inhibition by Y-27632 prevented CTGF and hydroxyproline, whereas the RhoA activator CN03 increased CTGF expression."

24469458

➶

medscan

"Together these results indicate that Y-27632 inhibits ROCK in Clear Cell Renal Cell Carcinoma and selectively targets Von Hippel Lindau-deficient Clear Cell Renal Cell Carcinoma while sparing Von Hippel Lindau-reconstituted Clear Cell Renal Cell Carcinoma in multiple genetic backgrounds."

27841867

➶

medscan

"However, Y-27632, a specific inhibitor of the protein kinase ROCK, significantly blocked apoptosis induced by phosphorylated FKHRL1 thr-32 (P < 0.01), which was mediated by L-NMMA."

17044646

➶

medscan

"Since Y-27632 inhibits both ROCK family members: ROCK1 and ROCK2, we sought to determine which ROCK was responsible for the synthetic lethal effect."

27841867

➶

medscan

"In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of transforming growth factor-β(1), thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells."

21986457

➶

trips

"Inhibition of ROCK by Y27632 suppressed the c-FLIPL-promoted motility by reducing phosphorylation of FAK and ERK."

18414015

Y-27632 inhibits ROCK. 5 / 5

| 3 1 1

➶

eidos

"Rho kinase inhibition by Y-27632 decreased aldosterone induced CTGF upregulation ( 52 + / -15 % ) ."

| PMC

➶

trips

"Inhibition of ROCK by Y-27632 inhibited the activity of RhoA and promoted the apoptosis."

22584506

➶

eidos

"Notably , inhibition of RhoA and ROCK by Tat-C3 and Y27632 , respectively , enhanced neurite outgrowth ( Fig. 3A ) [ [ 17 ] , [ 18 ] , [ 19 ] ] ."

32046944

➶

eidos

"As previously demonstrated in other cell types , nocodazole treatment triggered a global increase of RhoA activity and myosin light chain ( MLC ) phosphorylation ( Liu et al ., 1998 ; Takesono et al ., 2010 ; Fig. S2 , d and e ) , and pharmacological inhibition of the effector kinase Rho-associated protein kinase ( ROCK ) by Y27632 reverted this effect ."

32379884

➶

reach

"Enteroids, when required, were digested into 349 single cells using TrypLE and seeded into collagen-coated transwells (0.33cm 2 , 0.4μm 350 pore size, Polycarbonate, Fisher #07-200-147) in ROCK Inhibitor Y-27632 supplemented 351 maintenance media in 24-well plates."

| DOI

Sotrastaurin affects PKC

| 1 4 7

Sotrastaurin inhibits PKC.

| 1 4 5

Sotrastaurin inhibits PKC. 10 / 10

| 1 4 5

➶

reach

"AEB-071 (AEB) is a specific inhibitor of protein kinase C, which prevents T-lymphocyte activation."

19136892

➶

sparser

"Furthermore, inhibition of PKC by AEB071 significantly eliminated CCL2-induced elevated Nav1.8 currents."

24724624

➶

reach

"These results indicate that AEB071 inhibits PKC signaling in vivo, but that compensatory mechanisms prevent the suppression of the MAP-kinase pathway and that the treatment is not sufficient to completely stop cell proliferation or kill cells."

24141786

➶

reach

"These findings demonstrate AEB071 induced selective inhibition of the PKC and MAPK pathway in UM cells carrying GNAQ mutations."

22653968

➶

medscan

"These data further support the importance of protein kinase Cθ kinase activity in the oncogenic activity of triple-negative breast cancer cells, and the potential for clinical translation of protein kinase Cθ kinase inhibitors as a therapeutic option for patients with triple-negative breast cancer.Fig. 6Treatment with AEB071 inhibits protein kinase C θ activity and impairs growth of triple-negative breast cancer cells. a MDA-231-Luc-D3H2LN cells were treated with AEB071 at the indicated concentrations for 24 hours."

27663795

➶

sparser

"In the present study, we found that the inhibition of PKC by AEB071 significantly reduced the CCL2-induced Na v 1.8 peak current densities, and the in vitro PKC kinase assays also confirmed that PKC contributed to the phosphorylation of Na v 1.8 in response to CCL2."

24724624

➶

reach

"Combining two drugs may be useful as sotrastaurin mainly inhibits the PKC and NF-kappaB pathway, while TAC has a strong effect on the calcineurin and NFAT pathway and as it now seems also inhibits, though to a certain extent, the NF- kappaB pathway."

23573283

➶

reach

"Furthermore, inhibition of PKC by AEB071 significantly eliminated CCL2 induced elevated Nav1.8 currents."

24724624

➶

sparser

"However, the viral transcriptional activators HBx and PreS2-activator large surface protein have both been reported to trigger signaling processes involving PKC so that an anti-viral effect of PKC-inhibition by sotrastaurin would also be plausible xref , xref , xref ."

| 1 9

Dabrafenib inhibits cell population proliferation. 10 / 10

| 1 9

➶

reach

"35 The BRAF inhibitors Vemurafenib or Dabrafenib suppress proliferation of BRAF mutated melanoma cells, 36 but surprisingly Dabrafenib effectively suppresses RIPK3 activity as an off-target effect."

26355347

➶

reach

"In contrast to these compounds, the B-Raf V600E inhibitor dabrafenib selectively decreased proliferation of BRAF-mutant cell clones."

24885690

➶

reach

"Increased potency of encorafenib results in IC50 values of 40nmol/l or less in the majority of melanoma cell lines, whereas higher concentrations of dabrafenib (< 100nmol/l), and especially vemurafenib (< 1mumol/l) are necessary to inhibit proliferation of most cell lines [XREF_BIBR **]."

29356698

➶

reach

"We observed that the combination of vemurafenib or dabrafenib with TH1579 significantly reduced cell proliferation and induced cell death (p < 0.01) in A375, A375VR4, and ESTDAB049 cell lines compared with either treatment alone."

31919461

➶

reach

29455659

➶

reach

"XREF_BIBR The combination of dabrafenib with the PI3K and mTOR inhibitor decreased cell proliferation in both parental and resistant cell lines and offers a potential alternative treatment strategy in patients with acquired dabrafenib resistance."

24516336

➶

medscan

"RAF inhibitors such as vemurafenib and dabrafenib block BRAF-mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAF(V600E)-mutant melanoma. 46999999="V600E"}"

23288408

➶

reach

"While dabrafenib decreases cancer cell proliferation by inhibiting the oncogene BRAF V600E within tumor cells XREF_BIBR, pembrolizumab functions by increasing the immune systems T-cell response to tumor antigens XREF_BIBR."

29503892

➶

reach

"Co-treatment of both A100 and dabrafenib significantly suppressed in vitro cell proliferation and three- dimensional (3D) matrigel growth."

30588251

➶

| 1 1 1 8

Sotrastaurin inhibits cell population proliferation.

| 1 1 1 7

Sotrastaurin inhibits cell population proliferation. 10 / 10

| 1 1 1 7

➶

sparser

"Consistent with previous findings of selective regulation of T-cell development in PKC-θ − / − animal model, AEB071 inhibited TCR/CD28-mediated T-cell proliferation, GvHD and allograft rejection ( xref – xref ), but retained T-cell antiviral response ( xref )."

26528291

➶

reach

"Additionally, AEB071 attenuates BCR mediated survival pathways, inhibits CpG induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment mediated survival signaling pathways in primary CLL cells."

25001469

➶

medscan

"These results indicate that AEB071 inhibits protein kinase C signaling in vivo, but that compensatory mechanisms prevent the suppression of the MAP-kinase pathway and that the treatment is not sufficient to completely stop cell proliferation or kill cells."

24141786

➶

reach

"Like the combination of AEB071 + RAD001, combination of AEB071 and CGM097 further blocked cell proliferation compared to single agent treatment in most GNAQ/11 mutated cell lines."

27507190

➶

eidos

"90 This reduction might be related to inhibition of cell proliferation by AEB071 ."

22508161

➶

reach

"Preclinical studies demonstrated that sotrastaurin (AEB071) and enzastaurin, two adenosine triphosphate-competitive selective inhibitors of PKCbeta, induce apoptosis and inhibit the proliferation of BCR-subtypes of ABC-DLBCL in vitro and in vivo [XREF_BIBR, XREF_BIBR]."

26654227

➶

reach

"Drug screening in leukemia cell lines revealed that sotrastaurin (a PKC inhibitor) suppressed the proliferation of the FLT3-ITD-positive AML cell line MV4-11 but not of K562, HL60, or KG-1a cells, similar to SGI-1776 (a PIM-1 and FLT3 inhibitor) and quizartinib (an FLT3 inhibitor)."

30017192

➶

reach

26654227

➶

reach

"Consistent with previous findings of selective regulation of T-cell development in PKC-theta - / - animal model, AEB071 inhibited TCR and CD28 mediated T-cell proliferation, GvHD and allograft rejection, but retained T-cell antiviral response."

26528291

➶

reach

29497459

Sotrastaurin activates cell population proliferation.

| 1

Sotrastaurin activates cell population proliferation. 1 / 1

| 1

➶

reach

"A selective PKC inhibitor, sotrastaurin, effectively inhibited cell proliferation and induced cell apoptosis in a dose- and time dependent manner."

29534146

Sotrastaurin affects NFkappaB

| 11

Sotrastaurin inhibits NFkappaB.

| 10

Sotrastaurin inhibits NFkappaB. 10 / 10

| 10

➶

reach

22653968

➶

reach

"Sotrastaurin inhibited the NF-kappaB dependent cytokine production in the T cell subsets by 88.5%, 85.7%; and 88.0% respectively (p < 0.01 compared to no drug; XREF_FIG)."

23573283

➶

reach

"Furthermore, the PKC-theta inhibitor AEB071 inhibits NFkappaB and NFAT but not AP1 activity XREF_BIBR."

28317936

➶

reach

"Sotrastaurin inhibited NF-kappaB activation in the respective T cell subsets by 93%, 95% and 86% (p < 0.01 vs. no drug), while mycophenolic acid did not affect this activation pathway."

23573283

➶

reach

"These findings together indicate that AEB071 selectively inhibited NF-kappaB activation in UM cells harboring GNAQ mutations."

22653968

➶

reach

"AEB071 selectively inhibits NF-kappaB activity in GNAQ mutated UM cells."

22653968

➶

reach

"Sotrastaurin, a PKC-Theta inhibitor, was utilized to block NF-kappaB activation following TCR engagement, and was found to significantly inhibit TCR mediated chemotherapy resistance in T8ML-1 and in most primary TCL cells (XREF_SUPPLEMENTARY)."

27780854

➶

reach

"The downregulation of these PKC isoforms may contribute to AEB071 suppression of NF-kappaB activity."

22653968

➶

reach

"To confirm the involvement of PI3Kdelta and PKCbeta in the resistance to ATO, we first studied whether idelalisib and sotrastaurin inhibited the activation of Akt, NF-kappaB and STAT3."

26540567

➶

reach

23573283

Sotrastaurin dephosphorylates NFkappaB.

| 1

Sotrastaurin leads to the dephosphorylation of NFkappaB. 1 / 1

| 1

➶

reach

"Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kdelta and PKCbeta, respectively, inhibited Akt phosphorylation, NF-kappaB and STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO."

26540567

Momelotinib affects JAK2

1 1 | 3 6

Momelotinib inhibits JAK2.

1 1 | 3 5

Momelotinib inhibits JAK2. 10 / 10

1 1 | 3 5

➶

eidos

"Since tylophorine arrested IkappaBalpha mRNA , reduced IkappaBalpha protein expression , and liberated p65 ( Figs 2B , C and 5 ) , the diminishment of p65 phosphorylation via JAK2 inhibition by CYT387 ( Figs 2B-c and 6A ) was reasoned to be capable of working in an additive manner with tylophorine for anti-TGEV activity ( Figs 3 and 4 ) ."

28642467

➶

reach

"The addition of momelotinib suppressed paclitaxel induced JAK2 and STAT3 pathway activation in ovarian cancer cell lines."

29682172

➶

reach

"However, the discontinuation of paclitaxel and momelotinib treatment no longer suppressed JAK2 and STAT3 activation and CSC like development, thus allowing the resumption of tumor growth and dissemination."

29682172

➶

reach

"Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis."

28622623

➶

signor

No evidence text available

Other

➶

reach

"Momelotinib is a potent inhibitor of JAK1 and JAK2."

32394008

➶

tas

No evidence text available

19762238

➶

eidos

"We also found that JAK2 inhibition by CYT387 not only inhibited NF-kappaB activation ( p65 phosphorylation ) and subsequent cytokine production , e.g ."

28642467

➶

eidos

"JAK2 inhibition either by CYT387 ( a JAK family inhibitor ) or by silencing JAK2-expression revealed a dominant JAK2 mediated p65 phosphorylation pathway for NF-kappaB activation and resulted in NF-kappaB inhibition , which overrode the IkappaBalpha regulation via the IKK-2 ."

28642467

➶

reach

"28 Finally, momelotinib (also known as CYT-387) inhibits both JAK1 (IC 50 11 nm) and JAK2 (IC 50 18 nm), rather than JAK3 (IC 50 0.16 muM), although off-target effects (serine/threonine kinase IKBKE) have been described."

32676568

Momelotinib activates JAK2.

| 1

Momelotinib activates JAK2. 1 / 1

| 1

➶

reach

"Significant inhibition of JAK2 and STAT3 activation by 1muM momelotinib in both HEY and TOV21G cell lines was demonstrated by Western blot and immunofluorescence (XREF_SUPPLEMENTARY)."

29682172

Dabrafenib affects necroptotic process

| 2 9

Dabrafenib inhibits necroptotic process.

| 2 8

Dabrafenib inhibits necroptotic process. 10 / 10

| 2 8

➶

reach

"Dabrafenib mediated necroptosis suppression strongly correlated with its inhibitory effect on MLKL phosphorylation."

26355347

➶

reach

"Here, Dabrafenib blocks necroptosis by interference with RIPK3 mediated MLKL phosphorylation."

26355347

➶

reach

"However, dabrafenib did not ease apoptosis induced by TNFalpha plus Smac mimetic (TS) in HT29 cells (XREF_SUPPLEMENTARY), 4 further indicating that dabrafenib specifically inhibited the necroptosis pathway."

24901049

➶

reach

"Geserick et al. [XREF_BIBR] reported that Dabrafenib, a V600E- or V600K mutated porto-oncogene serine/threonine protein kinase B-RAF, inhibited necroptosis in melanoma cells whenever RIPK3 is present."

27429198

➶

reach

"Interestingly, recent studies have shown that the B-RAF V600E inhibitor dabrafenib has a function to selectively inhibit RIPK3 and prevents necroptosis in various disease models."

31817643

➶

reach

24901049

➶

reach

"XREF_BIBR Importantly, dabrafenib directly inhibits RIP3 kinase activity, in addition to TNF-alpha and NO induced necroptosis of keratinocytes."

30320198

➶

reach

"Dabrafenib can inhibit necroptosis of human hepatocytes incubated with APAP."

26549942

➶

medscan

"Moreover, only dabrafenib rescued cells from RIP3-mediated necroptosis induced by the necroptosis-induced combinations, that is, tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand or Fas ligand plus Smac mimetic and the caspase inhibitor z-VAD."

24901049

➶

medscan

"Here, Dabrafenib blocks necroptosis by interference with RIPK3-mediated MLKL phosphorylation."

26355347

Dabrafenib activates necroptotic process.

| 1

Dabrafenib activates necroptotic process. 1 / 1

| 1

➶

reach

"Furthermore, the inhibitor of mutant BRAF Dabrafenib, but not Vemurafenib, inhibited necroptosis in melanoma cells whenever RIPK3 is present."

26355347

Dabrafenib affects autophagy

| 11

Dabrafenib activates autophagy.

| 10

Dabrafenib activates autophagy. 10 / 10

| 10

➶

reach

"Additionally, dabrafenib caused autophagy in melanoma and this autophagic process was regulated by miR-26a via modifying HMGB1 expression."

31754297

➶

reach

"We treated the melanoma cell lines A375 and MEL624 with dabrafenib in the presence or absence of autophagy inhibitors, 3-methyladenosine, to determine if inhibition of autophagy induced by dabrafenib will affect the viability of melanoma cells to the drug."

27536070

➶

reach

"Dabrafenib induces both autophagy and ER stress in a dose dependent pattern in melanoma cells."

27536070

➶

reach

"In this study, first, we want to investigate whether dabrafenib can cause autophagy in two melanoma cell lines; second, whether this autophagy induced by dabrafenib is regulated by ER stress; and third, whether blocking ER stress and autophagy can increase the efficacy of dabrafenib in treating melanoma cells."

27536070

➶

reach

"In addition, autophagy signaling is also impaired by knocking down PERK, which supports our notion that dabrafenib induced autophagy is regulated by ER stress (XREF_FIG)."

27536070

➶

reach

"Our data demonstrated that autophagy was induced by dabrafenib in a dose dependent pattern and targeting dabrafenib induced autophagy overcame the drug resistance in melanoma cells."

27536070

➶

reach

"Taken together, we verified that dabrafenib triggers both autophagy and ER stress in both B-Raf inhibitor sensitive and B-Raf inhibitor resistant melanoma cells."

27536070

➶

reach

"Autophagy induced by dabrafenib protects the melanoma cells from the cytotoxicity of dabrafenib."

27536070

➶

reach

"Dabrafenib induced autophagy by downregulation of miR-26a following upregulation of HMGB1 in melanoma [XREF_BIBR]."

32340261

➶

reach

"Furthermore, silencing HMGB1 inhibited autophagy induced by dabrafenib in melanoma cells."

31754297

Dabrafenib inhibits autophagy.

| 1

Dabrafenib inhibits autophagy. 1 / 1

| 1

➶

reach

"Our data demonstrated that autophagy was induced by dabrafenib in a dose dependent pattern and targeting dabrafenib induced autophagy overcame the drug resistance in melanoma cells."

27536070

Dabrafenib affects Melanoma

1 | 10

Dabrafenib inhibits Melanoma.

1 | 9

Dabrafenib inhibits Melanoma. 9 / 9

| 9

➶

medscan

"The selective RAF inhibitors Vemurafenib (PLX4032) and GSK2118436 are clinically available and effective in melanomas with activating mutations in BRAF ( )."

22573716

➶

medscan

"Both vemurafenib and dabrafenib have significant clinical response in patients with BRafV600E/K melanoma ( , , )."

24664307

➶

medscan

"BRAF kinase inhibitors, such as PLX4032 and GSK-2118436, have shown anti-tumor activities in melanoma patients with BRAF mutations ( ; ; )."

24095280

➶

medscan

"While it is clear that BRAF inhibitor induce cutaneous squamous cell carcinoma with varying efficiency, it is unknown why this is the case, even though the most extensively tested inhibitors, vemurafenib and dabrafenib, appear to have similar efficacy in melanoma [ , - ]."

27028853

➶

medscan

"Recent clinical trials clarified that combined MEK (trametinib) and BRAF (dabrafenib) inhibition is effective molecular-targeted therapy for melanoma patients harbouring BRAF mutation, suggesting that the RSK-EphA2 pathway inhibition affects the therapeutic efficacy ."

26158630

➶

medscan

"While tumor mutation status is critical to outcomes of melanoma patients treated with selective BRAF inhibitors PLX4032 , and GSK2118436, its predictive significance for other therapies is largely unknown."

22130161

➶

medscan

"The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600E mutations."

28263969

➶

medscan

"The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600Emutations."

28263969

➶

medscan

23288408

Dabrafenib inhibits Melanoma. 1 / 1

1 |

➶

ctd

No evidence text available

23237741

Dabrafenib activates Melanoma.

| 1

Dabrafenib activates Melanoma. 1 / 1

| 1

➶

medscan

"The introduction into the clinical practice of vemurafenib and dabrafenib, potent inhibitors of BRAFV600 mutants, makes the assessment of BRAF mutations as a crucial step toward the appropriate use of a targeted melanoma treatment."

24885594

Dabrafenib affects MEK

| 11

Dabrafenib inhibits MEK.

| 5

Dabrafenib inhibits MEK. 3 / 3

| 3

➶

reach

"As such, the combination of BRAF plus MEK inhibition by dabrafenib plus trametinib appears to be an improvement on single-agent BRAF inhibition."

25018652

➶

reach

29420123

➶

reach

"AZ628 or Dabrafenib plus Trametinib enhanced MEK and ERK inhibition compared to single treatments."

29662630

Dabrafenib inhibits phosphorylated MEK. 2 / 2

| 2

➶

reach

"Moreover, dabrafenib increased p-C-Raf and decreased p-MEK1/2 and p-ERK in both cell lines (XREF_FIG)."

26630652

➶

reach

"Importantly, TAS-116 and dabrafenib synergistically inhibited p-MEK1/2 and p-ERK (XREF_FIG)."

26630652

Dabrafenib activates MEK.

| 4

Dabrafenib activates phosphorylated MEK. 2 / 2

| 2

➶

reach

"Importantly, TAS-116 enhanced the inhibition of p-MEK1/2 or p-ERK induced by dabrafenib."

26630652

➶

reach

26630652

Dabrafenib activates MEK. 2 / 2

| 2

➶

reach

"In fact, both vemurafenib and dabrafenib actually increase MEK and ERK activation in the setting of RAS mutations."

23438383

➶

reach

"In contrast, dabrafenib did not increase basal activity of MEK and ERK and efficiently suppressed light dependent activation of BRAF."

27025703

Dabrafenib phosphorylates MEK.

| 2

Dabrafenib leads to the phosphorylation of MEK. 2 / 2

| 2

➶

reach

"18Both dabrafenib and trametinib inhibit ERK and MEK phosphorylation in other models of BRAF mutation positive melanoma."

25797743

➶

reach

"In this case, dabrafenib did not inhibit but increased basal phosphorylation of MEK and ERK and further increased CRAF signaling induced by light exposure (XREF_FIG)."

27025703

Dabrafenib affects Neoplasm Invasiveness

| 10

Dabrafenib activates Neoplasm Invasiveness.

| 7

Dabrafenib activates Neoplasm Invasiveness. 7 / 7

| 7

➶

reach

"We describe a patient who presented vitreous infiltration of a cutaneous melanoma, who was effectively treated with dabrafenib."

28744830

➶

reach

"However, it abrogated up-regulation of ECM invasion induced by dabrafenib in this cell line."

29371923

➶

reach

"Moreover, both agents completely abrogated dabrafenib induced stimulation of ECM invasion."

| PMC

➶

reach

"Moreover, although dabrafenib still stimulated invasiveness in PTTG1 silenced A375R cells, ECM invasion by those cells was significantly reduced as compared to that of drug treated PTTG1 expressing cells."

29371923

➶

reach

"These results indicated that dabrafenib, when combined with pmel-1 ACT and IL-2, increases macrophage and Tregs infiltration in the tumor microenvironment, thus providing a potential mechanism for the suboptimal antitumor effect with this combination."

25787767

➶

reach

"Moreover, although 4 muM LEE011 did not affect A375R basal invasiveness, it abrogated stimulation of ECM invasion induced by dabrafenib in this cell line."

29371923

➶

reach

"In both cell lines, inhibition of invasiveness induced by dabrafenib alone was higher than that caused by PTTG1 silencing alone and similar to that induced by dabrafenib plus siPTTG1."

29371923

Dabrafenib inhibits Neoplasm Invasiveness.

| 3

Dabrafenib inhibits Neoplasm Invasiveness. 3 / 3

| 3

➶

reach

"Dabrafenib treatment markedly impaired ECM invasion in A375 and SK-Mel28 cells transfected with either siCTRL or siPTTG1."

29371923

➶

reach

"PTTG1 silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib induced stimulation of ECM invasion in A375R cells."

29371923

➶

reach

"A375 and A375R cells differently responded to dabrafenib, which strongly inhibited invasiveness and VEGF-A secretion in A375 cells, whereas it stimulated these functions in A375R cells."

| PMC

Sotrastaurin affects ERK

| 1 9

Sotrastaurin dephosphorylates ERK.

| 7

Sotrastaurin leads to the dephosphorylation of ERK. 7 / 7

| 7

➶

reach

"AEB071 selectively decreases Erk1/2 phosphorylation in UM cells harboring GNAQ mutations."

22653968

➶

reach

"We observed that the PKC inhibitor AEB071 inhibited ERK phosphorylation and cellular apoptosis in addition to PKC phosphorylation."

28548942

➶

reach

"Further, AEB071 (PKC inhibitor) and NAC (ROS scavenger) inhibited both ERK phosphorylation and caspase-3 activation."

28548942

➶

reach

"This is consistent with previous reports indicating that AEB071 inhibits ERK1/2 phosphorylation in GNAQ mutant cell lines."

24563540

➶

reach

"The ERK1/2 phosphorylation response to capsaicin was similarly suppressed by sotrastaurin."

29654770

➶

reach

"However, AEB071 only significantly inhibited Erk1/2 phosphorylation in GNAQ mutant cells while it had minimal effect on Akt phosphorylation in both GNAQ wild type and mutated cells (XREF_FIG)."

22653968

➶

reach

"AEB071 inhibited Erk1/2 phosphorylation in GNAQ mutated but not GNAQ wild type UM cells, and had minimal impact on Akt phophorylation."

22653968

Sotrastaurin inhibits ERK.

| 1 2

Sotrastaurin inhibits phosphorylated ERK. 2 / 2

| 1 1

➶

sparser

"Our studies indicate that both AEB071 and BYL719 can inhibit p-ERK as single agents or as part of combination therapy."

24563540

➶

reach

"Our studies indicate that both AEB071 and BYL719 can inhibit p-ERK as single agents or as part of combination therapy."

24563540

Sotrastaurin inhibits ERK. 1 / 1

| 1

➶

reach

"This was supported by our data that whereas the PKC inhibitor AEB071 inhibited G69-250-induced ERK and caspase-3 activation fully, the ROS scavenger NAC had no effect."

28548942

Sotrastaurin affects PRKCQ

4 | 1 1 3

Sotrastaurin inhibits PRKCQ. 9 / 9

4 | 1 1 3

➶

medscan

27663795

➶

tas

No evidence text available

21797275

➶

sparser

"Similar to genetic PKCtheta depletion, pharmacological PKCtheta inhibition by the PKC-selective inhibitor AEB071 (Sotrastaurin) [ xref ] significantly reduced the killing capacity of S. typhimurium -infected wild-type Mφ (Fig. xref )."

27465248

➶

reach

"AEB071 blocks the catalytic activity of PKCalpha, PKCbeta and PKCtheta isoforms at a low picomolar concentration range, as well as PKCdelta, PKCepsilon and PKCetaat higher, nanomolar, concentrations [XREF_BIBR]."

24892801

➶

tas

No evidence text available

➶

tas

No evidence text available

28131714

➶

tas

No evidence text available

19827831

➶

reach

"In agreement with these findings, PKCtheta was activated by EGF, insulin, and FBS, and the PKC inhibitor Sotrastaurin impaired the activation of PKCtheta and TBK1 (XREF_FIG and XREF_FIG, XREF_FIG)."

31792381

➶

reach

"AEB071 inhibits not only PKCtheta, but also other novel (Ca 2+ -independent delta, epsilon, and eta; nPKC) and conventional (Ca 2+ -dependent alpha and beta; cPKC) members at sub-nanomolar to low nanomolar concentrations, with a 1,000-10,000-fold lower selectivity for other kinases."

23433459

Sotrastaurin affects 2'-O-methyluridine

| 9

Sotrastaurin inhibits 2'-O-methyluridine.

| 6

Sotrastaurin inhibits 2'-O-methyluridine. 6 / 6

| 6

➶

reach

"We first examined whether p53 reactivation (Nutlin-3) in combination with PKC inhibition (Sotrastaurin) synergistically inhibits the growth of UM cells."

29593251

➶

reach

"These findings suggest that NF-kappaB activity is critically important for UM cells and its suppression contributes to AEB071 induced growth inhibition of UM cells harboring GNAQ mutations."

22653968

➶

reach

"The PKC inhibitor AEB071 selectively inhibits growth of UM cells harboring GNAQ mutations."

22653968

➶

reach

"Notably, AEB071 at low micromolar concentrations significantly inhibited the growth of UM cells harboring GNAQ mutations through induction of G1 arrest and apoptosis."

22653968

➶

reach

"AEB071 selectively inhibited the growth of UM cells harboring GNAQ mutations by targeting PKC/Erk1/2 and PKC and NF-kappaB pathways."

22653968

➶

reach

"Similarly, AEB071 decreased GSK3beta Ser9 phsophorylation in all UM cell lines studied here (XREF_SUPPLEMENTARY)."

22653968

Sotrastaurin activates 2'-O-methyluridine.

| 3

Sotrastaurin activates 2'-O-methyluridine. 3 / 3

| 3

➶

reach

"Metastatic UM patients (n = 153) were treated with AEB071 in a Phase I, single-arm study."

32029634

➶

reach

"To test this hypothesis, UM cells harboring wild type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus expressing shRNAs targeting PKC isoforms."

22653968

➶

reach

"In contrast, AEB071 did not increase Annexin V positive cell populations or caspase-3 cleavage in UM cells harboring wild type GNAQ (XREF_FIG)."

22653968

Dabrafenib affects RIPK3

| 4 5

Dabrafenib inhibits RIPK3.

| 4 4

Dabrafenib inhibits RIPK3. 8 / 8

| 4 4

➶

medscan

"Our data suggest that loss of RIPK3 in melanoma and selective inhibition of the RIPK3/MLKL axis by BRAF inhibitor Dabrafenib, but not Vemurafenib, is critical to protect from necroptosis."

26355347

➶

reach

"Indeed, the B-RAF inhibitor Dabrafenib has recently been shown to inhibit RIP3 independently of its effect on the B-RAF family members [XREF_BIBR]."

28978109

➶

reach

"In contrast to vemurafenib, it has been shown that dabrafenib inhibited RIPK3 activity in an ATP-competitive manner, and irrespectively of inhibition of BRAF mut [XREF_BIBR, XREF_BIBR]."

32340261

➶

medscan

"The BRAF inhibitors Vemurafenib or Dabrafenib suppress proliferation of BRAF-mutated melanoma cells, but surprisingly Dabrafenib effectively suppresses RIPK3 activity as an off-target effect."

26355347

➶

medscan

"Dabrafenib decreased the RIP3-mediated Ser358 phosphorylation of mixed lineage kinase domain-like protein (MLKL) and disrupted the interaction between RIP3 and MLKL."

24901049

➶

medscan

"Consistent with another recent study, Dabrafenib also interfered with RIPK3 activity in our study ( and ) and was able to block necroptosis and, to some extent, apoptosis."

26355347

➶

reach

"Since the B-RAF inhibitor Dabrafenib has recently been reported to inhibit RIP3 by its adenosine-5 '-triphosphate (ATP)-competitive binding to the enzyme [XREF_BIBR], we also tested the effect of Dabrafenib on the induction of necroptosis in AML cells."

28978109

➶

reach

"54 The B-Raf V600E inhibitors Vemurafenib and Dabrafenib inhibit RIPK3, with Dabrafenib being effective in the submicromolar range."

28661484

Dabrafenib binds RIPK3.

| 1

Dabrafenib binds RIPK3. 1 / 1

| 1

➶

reach

"B-Raf inhibitor dabrafenib binds to RIP3 in a cell-free system, but the low potency hinders its application in treating necroptosis involving diseases XREF_BIBR, XREF_BIBR."

30842407

Sotrastaurin affects activation

| 8

Sotrastaurin inhibits activation. 8 / 8

| 8

➶

sparser

"Sotrastaurin inhibits T-cell activation by peptide–MHC and CD28 co-stimulation in a PKC-dependent manner () and is currently in clinical trials for liver transplantation () and renal transplantation ()."

27179744

➶

sparser

"This was supported by our data that whereas the PKC inhibitor AEB071 inhibited G69-250-induced ERK and caspase-3 activation fully, the ROS scavenger NAC had no effect (Figure xref )."

28548942

➶

sparser

"This was to ensure that any AEB071 that would inhibit T responder cell activation was transferred along with the treated cells."

28531229

➶

sparser

"Sotrastaurin inhibited NF-κB activation in the respective T cell subsets by 93%, 95% and 86% (p<0.01 vs. no drug), while mycophenolic acid did not affect this activation pathway."

23573283

➶

sparser

"However, the finding that the combined deletion of PKCθ and PKCα primarily affects NFAT activation ( xref ) is inconsistent with findings that AEB071 does not inhibit NFAT activation ( xref )."

23433459

➶

sparser

"Sotrastaurin inhibits T-cell activation by peptide–MHC and CD28 co-stimulation in a PKC-dependent manner ( xref ; xref ) and is currently in clinical trials for liver transplantation ( xref ) and renal transplantation ( xref )."

27179744

➶

sparser

"AEB071 inhibits early T-cell activation via a calcineurin inhibitor independent pathway and is currently investigated as a therapeutic agent to prevent allograft rejection after renal transplantation."

19930311

➶

sparser

"These findings together indicate that AEB071 selectively inhibited NF-κB activation in UM cells harboring GNAQ mutations."

22653968

Sotrastaurin affects tacrolimus (anhydrous)

| 8

Sotrastaurin activates tacrolimus (anhydrous).

| 6

Sotrastaurin activates tacrolimus (anhydrous). 6 / 6

| 6

➶

reach

"Tacrolimus did not alter the pharmacokinetics of sotrastaurin; however, sotrastaurin increased tacrolimus area under the concentration-time curve by 2.0-fold (90% confidence interval, 1.8-2.1)."

20386017

➶

reach

"Tacrolimus exposure was significantly increased by sotrastaurin in the initial weeks posttransplant by a pharmacokinetic interaction."

21157403

➶

reach

"In clinical trials, it is recommended that patients administer sotrastaurin consistently either with or without food to avoid food-related fluctuations in drug exposure over time.157Clinical drug interaction studies to date have demonstrated that sotrastaurin increases the area under the concentration–time curve of everolimus (1.2-fold) and of tacrolimus (2-fold).158 Sotrastaurin increased tacrolimus concentration inasmuch as the tacrolimus dose needed to achieve a given C0 was up to 47% lower when combined with sotrastaurin versus MMF.158 Conversely, sotrastaurin area under the concentration–time curve is increased up to 1.8-fold by cyclosporine and 4.6-fold by ketoconazole.159PKC is a family of serine/threonine-specific protein kinases involved in diverse signal transduction pathways that modulate a whole range of cellular processes, including activation, proliferation, differentiation, apoptosis, and autophagy.160 PKC-θ has been shown to be essential in the T cell receptor/CD3 signal transduction pathway."

| PMC

➶

reach

"28 In these lines, it has been recently reported that tacrolimus does not alter the pharmacokinetics of sotrastaurin; however, sotrastaurin increases tacrolimus area under the concentration-time curve by twofold."

25028624

➶

reach

"Sotrastaurin increased tacrolimus concentrations by a pharmacokinetic interaction inasmuch as the tacrolimus dose needed to achieve a given C0 was up to 47% lower when combined with sotrastaurin versus with MPA."

21157403

➶

reach

"In clinical trials, it is recommended that patients administer sotrastaurin consistently either with or without food to avoid food-related fluctuations in drug exposure over time.123Clinical drug interaction studies to date have demonstrated that sotrastaurin increases the area under the concentration–time curve of everolimus (1.2-fold) and of tacrolimus (2-fold).124 Sotrastaurin increased tacrolimus concentration inasmuch as the tacrolimus dose needed to achieve a given C0 was up to 47% lower when combined with sotrastaurin versus MMF.124 Conversely, sotrastaurin area under the concentration–time curve is increased up to 1.8-fold by cyclosporine and 4.6-fold by ketoconazole.125PKC is a family of serine/threonine-specific protein kinases involved in diverse signal transduction pathways that modulate a whole range of cellular processes, including activation, proliferation, differentiation, apoptosis, and autophagy.231 PKC-θ has been shown to be essential in the T-cell receptor/CD3 signal transduction pathway."

| PMC

Sotrastaurin inhibits tacrolimus (anhydrous).

| 2

Sotrastaurin inhibits tacrolimus (anhydrous). 2 / 2

| 2

➶

reach

"124 Sotrastaurin increased tacrolimus concentration inasmuch as the tacrolimus dose needed to achieve a given C 0 was up to 47% lower when combined with sotrastaurin versus MMF."

| PMC

➶

reach

"158 Sotrastaurin increased tacrolimus concentration inasmuch as the tacrolimus dose needed to achieve a given C 0 was up to 47% lower when combined with sotrastaurin versus MMF."

| PMC

Dabrafenib affects Cell Survival

| 1 6

Dabrafenib inhibits Cell Survival.

| 1 3

Dabrafenib inhibits Cell Survival. 4 / 4

| 1 3

➶

medscan

"Dabrafenib selectively inhibits cell viability in B-RafV600E mutant cancer cells."

24885690

➶

reach

"Dabrafenib selectively inhibits cell viability in B-Raf V600E mutant cancer cells."

24885690

➶

reach

"Whereas increasing doses of PLX4032 or dabrafenib or E2F1 depletion alone reduced cell viability, combination of BRAF and E2F1 inhibition resulted in increased cell death in BRAF mutant lines."

29743521

➶

reach

"Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF (V600E)-mutant HT-29 cells and inhibits stem cell capacities."

29534162

Dabrafenib activates Cell Survival.

| 3

Dabrafenib activates Cell Survival. 3 / 3

| 3

➶

reach

"The result showed that dabrafenib reversed the reduction of the HT29 cell viability induced by TRAIL or Fas ligand plus Smac mimetic and z-VAD (SZ; XREF_FIG)."

24901049

➶

reach

"We harvested and examined cell viability by the Cell Counting Kit-8 and found that the group treated with only dabrafenib was more resistant to the drug in comparison to the group that was cotreated with 4-phenylbutyrate."

27536070

➶

reach

"BRAF inhibitor treatment alone suppressed cell survival more effectively than radiation in all the mutant V600E BRAF cell lines, and vemurafenib, but not dabrafenib, also inhibited cell survival in the WT BRAF cell lines at clinically relevant concentrations."

29491057

Dabrafenib affects CDK16

1 | 6

Dabrafenib inhibits CDK16.

1 | 5

Dabrafenib inhibits CDK16. 6 / 6

1 | 5

➶

reach

30992425

➶

reach

"The ability of dabrafenib to inhibit CDK16 was demonstrated by the ability of the vemurafenib-CDK16 siRNA combination to mimic the effects of dabrafenib on pRB and p27."

29112787

➶

reach

"However, given that dabrafenib and rebastinib are not specific inhibitors of CDK16, the identification or development of CDK16 selective inhibitors may be necessary."

28057719

➶

tas

No evidence text available

➶

reach

"Rebastinib and dabrafenib are potent inhibitors of CDK16."

28057719

➶

reach

"3.6 Dabrafenib mediated CDK16 inhibition enhances the cell cycle effects of NEK9 inhibition."

29112787

Dabrafenib binds CDK16.

| 1

Dabrafenib binds CDK16. 1 / 1

| 1

➶

reach

"We also found that the binding of CDK16 to dabrafenib and rebastinib was mutually exclusive with its binding to the cyclin Y/14-3-3 complex."

28057719

A-674563 affects AKT1

5 | 2

A-674563 inhibits AKT1.

5 |

A-674563 inhibits AKT1. 5 / 5

5 |

➶

tas

No evidence text available

20006497

➶

tas

No evidence text available

16678413

➶

tas

No evidence text available

22037378

➶

tas

| 1 5

➶

sparser

"AEB071, an inhibitor of PKCθ kinase activity, also inhibits growth and invasive branching of TNBC cells in 3-D cultures, further supporting a role for PKCθ kinase activity in triple-negative cancer cell growth."

27663795

➶

medscan

27663795

➶

sparser

"AEB071 selectively inhibited the growth of UM cells harboring GNAQ mutations by targeting PKC/Erk1/2 and PKC/NF-κB pathways."

22653968

➶

sparser

"The PKC inhibitor AEB071 selectively inhibits growth of UM cells harboring GNAQ mutations."

22653968

➶

sparser

"The PKC inhibitors AEB071 and AHT956 selectively inhibit the growth of GNAQ or GNA11 mutant melanoma cell lines."

24141786

➶

sparser

"AEB071 inhibits GNAQ Q209L -mediated tumor growth in vivo."

24141786

Momelotinib affects JAK1

1 2 | 3

Momelotinib inhibits JAK1. 6 / 6

1 2 | 3

➶

tas

No evidence text available

| DOI

➶

signor

No evidence text available

Other

➶

tas

No evidence text available

19762238

➶

reach

32676568

➶

reach

"Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis."

28622623

➶

reach

"Momelotinib is a potent inhibitor of JAK1 and JAK2."

32394008

Dabrafenib affects endoplasmic reticulum

| 6

Dabrafenib activates endoplasmic reticulum. 6 / 6

| 6

➶

reach

"We then assessed the dabrafenib induced ER stress response in both A375 and MEL624 cells."

27536070

➶

reach

"Taken together, we verified that dabrafenib triggers both autophagy and ER stress in both B-Raf inhibitor sensitive and B-Raf inhibitor resistant melanoma cells."

27536070

➶

reach

"Dabrafenib induces both autophagy and ER stress in a dose dependent pattern in melanoma cells."

27536070

➶

reach

"Therefore, our current studies support that dabrafenib induced ER stress can further activate autophagy and, therefore, provide multiple potential targets in the ER stress-autophagy link in melanoma treatment."

27536070

➶

reach

"Based on the fact that dabrafenib induces ER stress response in melanoma cells, we then tried to determine whether ER stress induced by dabrafenib will protect the cancer cells from the cytotoxicity of the drug."

27536070

➶

reach

"In our study on melanoma, we found that dabrafenib can induce ER stress and further activate autophagy."

27536070

Dabrafenib affects CYP3A4

| 1 5

Dabrafenib activates CYP3A4. 6 / 6

| 1 5

➶

reach

"As dabrafenib is a moderate inducer of CYP3A4 and all NNRTIs are substrates, NNRTIs are unlikely to reduce dabrafenib concentrations."

30815023

➶

eidos

"Because dabrafenib induces CYP3A4 and CYP2C9 it decreased the systemic exposures of the CYP3A4 substrate midazolam , the CYP2C9 substrate S-warfarin , and the CYP3A4 / CYP1A2 substrate R-warfarin ."

| PMC

➶

reach

"Because dabrafenib induces CYP3A4 and CYP2C9 it decreased the systemic exposures of the CYP3A4 substrate midazolam, the CYP2C9 substrate S-warfarin, and the CYP3A4/CYP1A2 substrate R-warfarin.XL281 (BMS-908662) is a highly selective inhibitor of B-RAF and C-RAF, but not A-RAF."

| PMC

➶

reach

"Because dabrafenib induces CYP3A4 and CYP2C9 it decreased the systemic exposures of the CYP3A4 substrate midazolam, the CYP2C9 substrate S-warfarin, and the CYP3A4/CYP1A2 substrate R-warfarin."

| PMC

➶

reach

"Dabrafenib induces CYP3A4 and thus may alter the metabolism of other medications metabolized through this pathway by reducing the bioavailability of substrates."

25089220

➶

reach

"Combined P-gp and strong CYP3A4 inducers such as carbamazepine, St John 's wort, dabrafenib, rifampin, and phenytoin can potentially decrease the anticoagulant efficacy of apixaban, so their combination with apixaban should be avoided."

25395835

Sotrastaurin affects MARCKS

| 2 4

Sotrastaurin inhibits MARCKS.

| 2 3

Sotrastaurin inhibits MARCKS. 5 / 5

| 2 3

➶

reach

"In these cells AEB071 inhibited p-MARCKS and p-S6 but induced activation of p-AKT over time, which was inhibited by BYL719 in the combination therapy."

24563540

➶

reach

"AEB071 inhibited p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status."

24563540

➶

sparser

"In these cells AEB071 inhibited p-MARCKS and p-S6 but induced activation of p-AKT over time, which was inhibited by BYL719 in the combination therapy."

24563540

➶

sparser

"AEB071 inhibited p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status."

24563540

➶

reach

"In all models, GNAQ/11 mutated and wt, AEB071 treatment led to decreased pMARCKS and pPKCdelta."

27507190

Sotrastaurin dephosphorylates MARCKS.

| 1

Sotrastaurin leads to the dephosphorylation of MARCKS. 1 / 1

| 1

➶

reach

"In the GNAQ-mutant cells, AEB071 decreased phosphorylation of MARCKS, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present."

24563540

Sotrastaurin affects ACE2

| 2 4

Sotrastaurin inhibits ACE2.

| 2 3

Sotrastaurin inhibits ACE2. 5 / 5

| 2 3

➶

reach

"∗P < 0.01 vs. 0, 2, 4, and 7.8 mM; ∗∗P < 0.05 vs. 0 and 2 mM; †P < 0.05 vs. 0 mM; n = 5.FIGURE 2: The pan-PKC inhibitor sotrastaurin reduces ACE2 shedding in mouse proximal tubular cells."

27313531

➶

reach

"On the other hand, sotrastaurin (10-5 M) completely inhibited ACE2 shedding under conditions of high D-glucose (28 mM), to levels observed under basal conditions, with or without TAPI-1 (Figure 2C)."

27313531

➶

reach

"On the other hand, sotrastaurin (10 -5 M) completely inhibited ACE2 shedding under conditions of high D-glucose (28 mM), to levels observed under basal conditions, with or without TAPI-1."

27313531

➶

sparser

"In cells maintained in 7.8 mM D -glucose, ACE2 shedding was significantly inhibited by the pan-protein kinase C (PKC) competitive inhibitor sotrastaurin, but not by an inhibitor of ADAM17."

27313531

➶

sparser

"In cells maintained in 7.8 mM D-glucose, ACE2 shedding was significantly inhibited by the pan-protein kinase C (PKC) competitive inhibitor sotrastaurin, but not by an inhibitor of ADAM17."

27313531

Sotrastaurin activates ACE2.

| 1

Sotrastaurin activates ACE2. 1 / 1

| 1

➶

reach

"* P < 0.01 vs. 0, 2, 4, and 7.8 mM; * * P < 0.05 vs. 0 and 2 mM; † P < 0.05 vs. 0 mM; n = 5.The pan-PKC inhibitor sotrastaurin reduces ACE2 shedding in mouse proximal tubular cells."

27313531

Momelotinib affects STAT3

| 6

Momelotinib inhibits STAT3.

| 5

Momelotinib inhibits STAT3. 5 / 5

| 5

➶

reach

"Conversely, momelotinib (JAK inhibitor) effectively inhibited STAT3 activation in A549 cells."

29576846

➶

reach

"The addition of momelotinib suppressed paclitaxel induced JAK2 and STAT3 pathway activation in ovarian cancer cell lines."

29682172

➶

reach

"The addition of daily momelotinib to weekly paclitaxel treatment significantly inhibited the JAK2 and STAT3 activation and CSC like phenotypes in mice tumors."

29682172

➶

reach

29682172

➶

reach

"However, momelotinib effectively inhibited STAT3 activation suggesting that JAK-2 activation plays an important role in STAT3 activation in A549 cells."

29576846

Momelotinib activates STAT3.

| 1

Momelotinib activates STAT3. 1 / 1

| 1

➶

reach

"Significant inhibition of JAK2 and STAT3 activation by 1muM momelotinib in both HEY and TOV21G cell lines was demonstrated by Western blot and immunofluorescence (XREF_SUPPLEMENTARY)."

29682172

Dabrafenib affects extracellular matrix

| 6

Dabrafenib activates extracellular matrix.

| 4

Dabrafenib activates extracellular matrix. 4 / 4

| 4

➶

reach

"Moreover, both agents completely abrogated dabrafenib induced stimulation of ECM invasion."

| PMC

➶

reach

"In both siCTRL and A375R and siPTTG1 and A375R cells, exposure to dabrafenib promoted ECM invasion."

29371923

➶

reach

"However, it abrogated up-regulation of ECM invasion induced by dabrafenib in this cell line."

29371923

➶

reach

"Moreover, although 4 muM LEE011 did not affect A375R basal invasiveness, it abrogated stimulation of ECM invasion induced by dabrafenib in this cell line."

29371923

Dabrafenib inhibits extracellular matrix.

| 2

Dabrafenib inhibits extracellular matrix. 2 / 2

| 2

➶

reach

"PTTG1 silencing also impaired proliferation and invasiveness of A375R and SK-Mel28R cells, and counteracted dabrafenib induced stimulation of ECM invasion in A375R cells."

29371923

➶

reach

"Dabrafenib treatment markedly impaired ECM invasion in A375 and SK-Mel28 cells transfected with either siCTRL or siPTTG1."

29371923

Dabrafenib affects cell growth

| 1 5

Dabrafenib inhibits cell growth.

| 4

Dabrafenib inhibits cell growth. 4 / 4

| 4

➶

reach

"The combination of dabrafenib and trametinib suppressed cell growth in the resistant lines."

23085539

➶

reach

"In a preclinical study, dabrafenib plus trametinib synergistically inhibited cell growth in a BRAF V600E-mutant lung carcinoma cell line (MV522; data on file)."

27283860

➶

reach

"The durability of these responses was determined by 4-week colony formation assays in which dabrafenib completely suppressed the WM1366 cell growth, but vemurafenib did not."

29112787

➶

reach

"Furthermore, treatment of dabrafenib resistant melanoma cells with BRAF inhibitor in combination with phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 inhibited cell growth (Greger et al., 2012)."

24325952

Dabrafenib activates cell growth.

| 1 1

Dabrafenib activates cell growth. 2 / 2

| 1 1

➶

reach

"Both SK-MEL-28VR1 and 501-mel cells showed a reduction in cell growth when simultaneously treated with MTX and dabrafenib compared to MTX or dabrafenib single treatments or vehicle only treatments."

29568360

➶

medscan

"Combination of dabrafenib with AKTi enhances cell growth inhibition in dabrafenib sensitive (A) and resistant cell lines (B) but not in very sensitive cell lines (C)."

24735930

Dabrafenib affects Neoplasms

| 6

Dabrafenib inhibits Neoplasms.

| 4

Dabrafenib inhibits Neoplasms. 4 / 4

| 4

➶

medscan

"In addition, dabrafenib and trametinib treatment of CD73+BRAFV600E-mutant melanomas caused profound CD73 downregulation in tumor cells."

28652244

➶

medscan

"Dabrafenib selectively inhibits cell viability in B-RafV600E mutant cancer cells."

24885690

➶

medscan

"Combined treatment with dabrafenib and trametinib was able to overcome resistance in preclinical models and use in patients with B-RAF mutated tumors resulted in improved progression free survival [ ]."

24588908

➶

medscan

"BRAF pathway plays an important role in tumorigenesis in non-small cell lung cancer, BRAF inhibitors, vemurafenib and dabrafenib have shown only modest efficacy in BRAF-V600E mutant cancers [ , ]. 46999999="V600E"}"

25706985

Dabrafenib activates Neoplasms.

| 2

Dabrafenib activates Neoplasms. 2 / 2

| 2

➶

medscan

"Monotherapy with vemurafenib, dabrafenib, and encorafenib induces neoplasia, most often cutaneous squamous cell carcinoma , at rates of approximately 22%, 6%, and 3.7%, respectively [ , - ], averaged across multiple phase I-III trials conducted in heterogeneous patient populations."

27028853

➶

medscan

"Recent clinical evidence suggest that Vemurafenib and GSK2118436 therapy enhances CD8+ T cell infiltration of the tumor mass, which correlates with the degree of tumor shrinkage ( )."

22850568

Y-27632 affects RHOA

| 4 2

Y-27632 inhibits RHOA.

| 4

Y-27632 inhibits RHOA. 4 / 4

| 4

➶

medscan

"We found that blockade of RhoA with C3 exoenzyme or inhibition of RhoA kinase by the specific inhibitor Y-27632 enhanced phorbol ester-stimulated alpha(4)beta(1)-dependent adhesion of Jurkat cells at 30 min."

12193698

➶

medscan

22842919

➶

medscan

23963366

➶

medscan

"RhoA siRNA and RhoA activation inhibitor, Y-27632, markedly reduce the angiotensin II effect."

16684954

Y-27632 activates RHOA.

| 2

Y-27632 activates RHOA. 2 / 2

| 2

➶

reach

"We also noted that feeder cells and altered molecular pathways activate telomerase (Fu et al. 2003; Liu et al. 2008; Liu et al. 2009; Klingelhutz and Roman 2012; Liu et al. 2012), and a Rho-Kinase inhibitor, Y-27632, disrupts the actin cytoskeleton and inactivate Rho (Chapman et al. 2010; Liu et al. 2012)."

| PMC

➶

reach

22842919

Sotrastaurin affects PRKCB

3 2 | 1

Sotrastaurin inhibits PRKCB.

3 1 | 1

Sotrastaurin inhibits PRKCB. 4 / 4

3 | 1

➶

tas

No evidence text available

21797275

➶

reach

24892801

➶

tas

No evidence text available

28131714

➶

tas

No evidence text available

19827831

Sotrastaurin inhibits PRKCB. 1 / 1

1 |

➶

ctd

No evidence text available

25634538

Sotrastaurin phosphorylates PRKCB.

1 |

Sotrastaurin phosphorylates PRKCB. 1 / 1

1 |

➶

ctd

No evidence text available

25634538

Dabrafenib affects MAP2K1

| 6

Dabrafenib inhibits MAP2K1.

| 2

Dabrafenib inhibits MAP2K1. 2 / 2

| 2

➶

reach

"Finally, dabrafenib and trametinib are small molecule inhibitors of BRAF and MEK1 and MEK2, respectively."

28848703

➶

reach

"The combination of dabrafenib and rigosertib appeared to suppress the positive regulation and promote the negative regulation of MEK1."

29968772

Dabrafenib phosphorylates MAP2K1.

| 2

Dabrafenib leads to the phosphorylation of MAP2K1 on T286. 1 / 1

| 1

➶

reach

"The combination of dabrafenib and rigosertib suppressed the positively regulated phosphorylation of MEK1 at Ser217/221 and ERK1/2 at Thr202 and Tyr204, promoted the negatively regulated phosphorylation of MEK1 at Thr286, and maintained the negatively regulated phosphorylation of MEK1 at Thr292 and Thr386."

Sotrastaurin affects PRKCD

3 | 2

Sotrastaurin inhibits PRKCD.

3 | 1

Sotrastaurin inhibits PRKCD. 4 / 4

3 | 1

➶

tas

No evidence text available

28131714

➶

tas

No evidence text available

19827831

➶

reach

24892801

➶

tas

No evidence text available

21797275

Sotrastaurin activates PRKCD.

| 1

Sotrastaurin activates PRKCD. 1 / 1

| 1

➶

reach

"Sotrastaurin attenuates the stemness of gastric cancer cells by targeting PKCdelta."

31261030

Dabrafenib affects hPXR

| 2 1 2

Dabrafenib activates hPXR.

| 1 1 2

Dabrafenib activates hPXR. 4 / 4

| 1 1 2

➶

reach

"Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR."

32650447

➶

eidos

"Using different reporter cellular assays , we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813 , whereas it does not activate mouse or zebrafish PXR nor hCAR ."

32650447

➶

reach

"In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet."

32650447

➶

isi

32650447

Dabrafenib binds hPXR.

| 1

Dabrafenib binds hPXR. 1 / 1

| 1

➶

isi

32650447

Dabrafenib affects cell death

| 5

Dabrafenib activates cell death.

| 4

Dabrafenib activates cell death. 4 / 4

| 4

➶

reach

"In addition, z-VAD increased cell death induced by acetaminophen, which was prevented by dabrafenib partly (XREF_SUPPLEMENTARY); dabrafenib but not vemurafenib decreased the acetaminophen induced loss of the cell viability (XREF_SUPPLEMENTARY)."

24901049

➶

reach

31919461

➶

reach

"ER stress response plays a protective role and provides resistance to dabrafenib mediated cell death in melanoma."

27536070

➶

reach

26029997

Dabrafenib inhibits cell death.

| 1

Dabrafenib inhibits cell death. 1 / 1

| 1

➶

reach

"We observed that pretreatment of cells with Nec1s, as well as an RIPK3 inhibitor dabrafenib, prevented crystalline particle induced cell death."

29138474

Dabrafenib affects cell cycle

| 1 4

Dabrafenib activates cell cycle.

| 4

Dabrafenib activates cell cycle. 4 / 4

| 4

➶

reach

"FACS cell cycle analysis revealed that 25 nM dabrafenib induced G0/G1 cell cycle arrest of the A375 cells, but not the A375R cells."

29956724

➶

reach

"Next, we examined the cell cycle profiles of BRAFi resistant MM cells treated with MTX + dabrafenib drug combinations."

29568360

➶

reach

"Vemurafenib, encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines; however, a residual population of tumor cells survive."

32629178

➶

reach

"Like vemurafenib, dabrafenib decreases phosphorylated ERK and causes cell cycle arrest."

24516336

Dabrafenib inhibits cell cycle.

| 1

Dabrafenib inhibits cell cycle. 1 / 1

| 1

➶

eidos

"Vemurafenib , encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines ; however , a residual population of tumor cells survive ."

32629178

Dabrafenib affects Multiple Myeloma

| 5

Dabrafenib activates Multiple Myeloma.

| 4

Dabrafenib activates Multiple Myeloma. 4 / 4

| 4

➶

reach

"TAS-116 also enhanced dabrafenib induced MM cytotoxicity associated with mitochondrial damage induced apoptosis, even in the BRAF mutated U266 MM cell line."

26630652

➶

reach

"Taken together, these results indicate that TAS-116 enhances dabrafenib induced MM cytotoxicity and apoptosis, even in the BRAF mutated U266 MM cells."

26630652

➶

reach

"Because HSP90 inhibitors block multiple pathways crucial to MM survival [XREF_BIBR, XREF_BIBR, XREF_BIBR], the combination of TAS-116 and dabrafenib enhances the anti-MM effect in RAS mutated and wild-type BRAF MM cells via a mechanism other than ERK pathway inhibition."

26630652

➶

reach

"Next, we examined the cell cycle profiles of BRAFi resistant MM cells treated with MTX + dabrafenib drug combinations."

29568360

Dabrafenib inhibits Multiple Myeloma.

| 1

Dabrafenib inhibits Multiple Myeloma. 1 / 1

| 1

➶

reach

"TAS-116 or dabrafenib significantly inhibited the viability of U266 MM cells in a dose- and time dependent manner (XREF_FIG)."

26630652

Sotrastaurin affects Receptors, Antigen, B-Cell

| 5

Sotrastaurin inhibits Receptors, Antigen, B-Cell.

| 3

Sotrastaurin inhibits Receptors, Antigen, B-Cell. 2 / 2

| 2

➶

reach

"In contrast, BCR pathway inhibitors such as ibrutinib, idelalisib, duvelisib, MK2206, AEB-071, dasatinib or alkylating agent such as bend-amustine did not result in synergy [XREF_BIBR, XREF_BIBR]."

26440741

➶

reach

25001469

Sotrastaurin inhibits mutated Receptors, Antigen, B-Cell. 1 / 1

28486107

Sotrastaurin inhibits RASGRP3.

| 2

Sotrastaurin inhibits RASGRP3. 2 / 2

| 2

➶

reach

"The PKC inhibitors AEB071 and AHT956 also both decreased RasGRP3 mRNA, also with no effect on SOS1 mRNAs (XREF_SUPPLEMENTARY)."

28486107

➶

reach

"The PKC inhibitors AEB071 and AHT956 also both decreased RasGRP3 mRNA, also with no effect on SOS1 mRNAs."

28486107

Dabrafenib affects AKT

| 5

Dabrafenib activates AKT.

| 3

Dabrafenib activates AKT. 2 / 2

| 2

➶

reach

27713119

➶

reach

"Lapatinib blocked the superactivated HER2 and HER3, AKT and pERK1/2 induced by dabrafenib."

sparser

"This is consistent with previous reports indicating that AEB071 inhibits ERK1/2 phosphorylation in GNAQ mutant cell lines ( xref )."

24563540

➶

sparser

"AEB071 inhibited Erk1/2 phosphorylation in GNAQ mutated but not GNAQ wild type UM cells, and had minimal impact on Akt phophorylation."

22653968

➶

sparser

"However, AEB071 only significantly inhibited Erk1/2 phosphorylation in GNAQ mutant cells while it had minimal effect on Akt phosphorylation in both GNAQ wild type and mutated cells ( xref )."

22653968

Sotrastaurin affects PRKCE

3 | 1

Sotrastaurin inhibits PRKCE. 4 / 4

3 | 1

➶

tas

No evidence text available

21797275

➶

tas

No evidence text available

19827831

➶

reach

24892801

➶

tas

No evidence text available

28131714

Sotrastaurin affects PRKCA

3 | 1

Sotrastaurin inhibits PRKCA. 4 / 4

3 | 1

➶

reach

24892801

➶

tas

No evidence text available

19827831

➶

tas

No evidence text available

21797275

➶

tas

No evidence text available

28131714

Dabrafenib affects mtnN

| 4

Dabrafenib activates mtnN. 4 / 4

| 4

➶

reach

"Copy number changes in CDKN2A, CCND1, and mutation and copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib."

23833299

➶

reach

"The combination of dabrafenib with trametinib significantly increased PFS over dabrafenib alone in a phase II study [XREF_BIBR]."

25344914

➶

reach

"Median PFS was significantly improved at 9.4 months for the patients treated with 150mg dabrafenib twice daily and 2mg trametinib daily, as compared with 5.8 months for the patients treated with dabrafenib alone (HR for progression or death, 0.39; 95% CI, 0.25-0.62; P < 0.001)."

26217117

➶

reach

"Increased cyclin D expression mediates inherent resistance to mutant BRAF inhibition [XREF_BIBR], and copy number changes in CDKN2A, CCND1 correlated with the shortened duration of PFS in patients treated with dabrafenib [XREF_BIBR]."

24743024

Dabrafenib affects PTEN

| 4

Dabrafenib activates PTEN. 4 / 4

| 4

➶

reach

"In a study by Nathanson et al. [XREF_BIBR], patients with wild-type PTEN treated with BRAF inhibitor dabrafenib had longer PFS compared with patients with at least one mutated allele of PTEN (32.1 vs 18.3 weeks; p = 0.066), and a modest association between low expression of PTEN and lower response was observed in the phase 2 study of vemurafenib as well [XREF_BIBR]."

25344914

➶

reach

"Furthermore, she showed data on PTEN as a marker of progression-free survival among patients treated with dabrafenib."

24650043

➶

reach

"Copy number changes in CDKN2A, CCND1, and mutation and copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib."

23833299

➶

reach

"On the other hand, tissue expression of PTEN was associated with shorter PFS in patients treated with dabrafenib [XREF_BIBR]."

26171394

Brivanib affects cell population proliferation

| 4

Brivanib inhibits cell population proliferation. 4 / 4

| 4

➶

medscan

"To determine whether brivanib inhibits growth factor-induced proliferation of hepatic stellate cells, we examined the effect of increasing concentrations of brivanib on LX-2 hepatic stellate cell proliferation under control conditions or after stimulation with concentrations of platelet-derived growth factor, VEGF, and FGF2 shown to induce LX-2 proliferation."

24710173

➶

medscan

"Our findings demonstrate that brivanib reduces liver fibrosis in three different animal models, and inhibits growth factor-induced stellate cell proliferation and activation."

24710173

➶

medscan

"Our findings that brivanib inhibits not only VEGF- and fibroblast growth factor-mediated proliferation of hepatic stellate cells, but also inhibits platelet-derived growth factor-induced proliferation, together with our other findings that brivanib abrogates phosphorylation of the platelet-derived growth factorβ receptor, suggest the need to further characterize the modulation of platelet-derived growth factor signaling by brivanib."

24710173

➶

medscan

"In vitro, brivanib decreased proliferation of hepatic stellate cells induced by platelet-derived growth factor , VEGF, and FGF."

24710173

A-674563 affects PRKACA

3 1 |

A-674563 inhibits PRKACA. 4 / 4

3 1 |

➶

drugbank

No evidence text available

10592235

➶

tas

No evidence text available

➶

tas

No evidence text available

16678413

➶

tas

No evidence text available

22037378

Sotrastaurin affects everolimus

| 4

Sotrastaurin activates everolimus.

| 3

Sotrastaurin activates everolimus. 3 / 3

| 3

➶

reach

"Sotrastaurin exposure does not seem to be altered by everolimus, but sotrastaurin increases everolimus exposure by 20%."

25028624

➶

reach

"Sotrastaurin increased everolimus C (max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng * h/ml yielding a ratio of 1.20 (1.05 - 1.37)."

20137762

➶

reach

"Everolimus AUC was increased 20% by sotrastaurin."

20137762

Sotrastaurin increases the amount of everolimus.

| 1

Sotrastaurin increases the amount of everolimus. 1 / 1

| 1

➶

reach

"The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels can not be excluded."

20137762

Sotrastaurin affects cell cycle

| 4

Sotrastaurin activates cell cycle.

| 3

Sotrastaurin activates cell cycle. 3 / 3

| 3

➶

reach

"This is important since higher concentrations of AEB071 are known to cause cell cycle perturbations and apoptosis in certain cell types."

26420215

➶

reach

"The protein kinase C (PKC) inhibitor sotrastaurin induced cell cycle arrest and/or cell death in ABC DLBCL cell lines and in a mouse xenograft model [XREF_BIBR]."

26010601

➶

reach

"Furthermore, we demonstrated that the PKC inhibitor sotrastaurin induced cell apoptosis and cell cycle arrest in DLBCL cells potentially through regulating the expression of MCT-1."

29534146

Sotrastaurin inhibits cell cycle.

| 1

Sotrastaurin inhibits cell cycle. 1 / 1

| 1

➶

reach

"Inhibition of PKC alone such as by AEB071 or sotrastaurin induced cell cycle G1 phase arrest and suppressed PKC and ERK1/2 signaling."

28223438

Momelotinib affects Neoplastic Stem Cells

| 4

Momelotinib inhibits Neoplastic Stem Cells.

| 3

Momelotinib inhibits Neoplastic Stem Cells. 3 / 3

| 3

➶

reach

"Momelotinib significantly suppressed the development of CSC like markers associated with paclitaxel treatment in ovarian cancer cell lines."

29682172

➶

reach

29682172

➶

reach

"The addition of daily momelotinib to weekly paclitaxel treatment significantly inhibited the JAK2 and STAT3 activation and CSC like phenotypes in mice tumors."

29682172

Momelotinib decreases the amount of Neoplastic Stem Cells.

| 1

Momelotinib decreases the amount of Neoplastic Stem Cells. 1 / 1

| 1

➶

reach

"Phase 1 : Daily momelotinib administration in conjunction with weekly paclitaxel significantly reduced in vivo expression of CSC markers and associated tumorigenicity of HEY cells in mice."

29682172

Momelotinib affects JAK

| 4

Momelotinib inhibits JAK.

| 3

Momelotinib inhibits JAK. 3 / 3

| 3

➶

reach

"Furthermore, IGF1R inhibitors such as linsitinib (OSI-906), MEK inhibitors such as selumetinib (AZD6244) or trametinib (GSK1120212) and JAK and TBK1 inhibitors such as momelotinib (CYT387) each have a unique side effect profile and sets of nonoverlapping toxicities."

25303301

➶

reach

"JAK family inhibitors like TG101209 or momelotinib (formerly Cytopia387) have been shown to partially normalize cytokine concentrations in mice with JAK2 V617F -induced MPN."

25912019

➶

reach

"Conversely, JAK and STAT signaling was selectively activated in CBL iPSCs and abrogated by the JAKi momelotinib and ruxolitinib."

29884903

Momelotinib activates JAK.

| 1

Momelotinib activates JAK. 1 / 1

| 1

➶

reach

"Momelotinib therapy targets the JAK and STAT family, a key prosurvival pathway that controls apoptotic signals in hematological malignancies [XREF_BIBR]."

32394008

Dabrafenib affects RAF

| 4

Dabrafenib inhibits RAF.

| 3

Dabrafenib inhibits RAF. 3 / 3

| 3

➶

reach

"In case of light induced BRAF, vemurafenib enhanced and dabrafenib inhibited the RAF kinase cascade activity."

27025703

➶

reach

"Higher concentrations of dabrafenib inhibited RAF signaling without further affecting the level of CRAF proteins."

27025703

➶

reach

"Approved Raf kinase inhibitors, such as dabrafenib and vemurafenib, are ineffective inhibitors of c-Raf and so clinical testing of this hypothesis will have to await the emergence of true c-Raf inhibitor drugs."

25520658

Dabrafenib activates RAF.

| 1

Dabrafenib activates RAF. 1 / 1

| 1

➶

reach

"In contrast, in CRAF-CRY2 expressing cells dabrafenib induced paradoxical activation of RAF signaling in dark which was even more pronounced upon light exposure."

27025703

A-674563 affects CDK2

3 | 1

A-674563 inhibits CDK2.

3 |

A-674563 inhibits CDK2. 3 / 3

3 |

➶

tas

No evidence text available

16678413

| 2

A-674563 increases the amount of phosphorylated AKT. 2 / 2

| 2

➶

reach

"p-AKT levels are decreased by MK-2206 and increased by A-674563."

29470540

➶

reach

"A-674563 was found to increase the expression of p-AKT (Ser473) and p-AKT (Thr308) in both cell lines."

29470540

Sotrastaurin affects PKC isoforms

| 4

Sotrastaurin inhibits PKC isoforms.

| 2

Sotrastaurin inhibits PKC isoforms. 2 / 2

| 2

➶

reach

"To better understand differential responses of UM cells to AEB071 based on GNAQ mutational status, we examined inhibition of PKC isoforms by AEB071 in UM cells."

| 2

Dabrafenib inhibits TNF. 2 / 2

| 2

➶

reach

"Dabrafenib blocked lipopolysaccharides induced activation of TNF-alpha in bone marrow derived macrophages, suggesting that Dabrafenib may attenuate TNF-alpha-induced necroptotic pathway after ischemic brain injury."

| 1 2

➶

sparser

"Sotrastaurin inhibited the NF-κB dependent cytokine production in the T cell subsets by 88.5%, 85.7%; and 88.0% respectively (p<0.01 compared to no drug; xref )."

23573283

➶

reach

"Sotrastaurin inhibited the NF-kappaB dependent cytokine production in the T cell subsets by 88.5%, 85.7%; and 88.0% respectively (p < 0.01 compared to no drug; XREF_FIG)."

23573283

➶

reach

"Sotrastaurin prevented TCR and CD28 induced T-cell activation and pro inflammatory cytokine production, but preserved a stable Treg phenotype as evidenced by maintenance of suppressive capacity, high Foxp3 and CD25 expression, and lack of IL-17A and IFNgamma production."

24192715

Sotrastaurin affects RPS6

| 1 2

Sotrastaurin inhibits RPS6. 3 / 3

| 1 2

➶

sparser

"AEB071 inhibited p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status."

24563540

➶

reach

"AEB071 inhibited p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status."

24563540

➶

reach

"In these cells AEB071 inhibited p-MARCKS and p-S6 but induced activation of p-AKT over time, which was inhibited by BYL719 in the combination therapy."

24563540

Sotrastaurin affects PRKCH

3 |

Sotrastaurin inhibits PRKCH. 3 / 3

3 |

➶

tas

No evidence text available

21797275

➶

tas

No evidence text available

19827831

➶

tas

No evidence text available

28131714

Sotrastaurin affects NFAT

| 1 2

Sotrastaurin inhibits NFAT. 3 / 3

| 1 2

➶

reach

"Furthermore, the PKC-theta inhibitor AEB071 inhibits NFkappaB and NFAT but not AP1 activity XREF_BIBR."

28317936

➶

reach

"However, the finding that the combined deletion of PKCtheta and PKCalpha primarily affects NFAT activation is inconsistent with findings that AEB071 does not inhibit NFAT activation."

23433459

➶

sparser

"Furthermore, the PKC-θ inhibitor AEB071 inhibits NFκB and NFAT but not AP1 activity xref ."

28317936

Sotrastaurin affects GSK3B

2 | 1

Sotrastaurin inhibits GSK3B. 3 / 3

2 | 1

➶

reach

"Similarly, AEB071 decreased GSK3beta Ser9 phsophorylation in all UM cell lines studied here (XREF_SUPPLEMENTARY)."

22653968

➶

tas

No evidence text available

➶

tas

No evidence text available

19827831

Sotrastaurin affects ABC-DLBCL

| 3

Sotrastaurin inhibits ABC-DLBCL. 3 / 3

| 3

➶

reach

26654227

➶

reach

26654227

➶

reach

26654227

Momelotinib affects apoptotic process

| 3

Momelotinib activates apoptotic process. 3 / 3

| 3

➶

reach

"Furthermore, apoptosis induced by momelotinib treatment was suppressed by LKB1 re-expression in KL A549 cells."

30205046

➶

reach

"Indeed, single-agent momelotinib treatment induced apoptosis in KL and KLP but not in KP cells."

30205046

➶

reach

"In the sensitive cell lines (WSU-NHL, RL, Karpas-422, Jeko-1, and L540) the citarinostat+ momelotinib combination induced apoptosis mediated by the intrinsic (mitochondrial) apoptotic pathway."

32394008

Dabrafenib affects TLE5

| 3

Dabrafenib activates TLE5. 3 / 3

| 3

➶

reach

"The most common AEs noted in patients treated with dabrafenib were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%) and skin papillomas (24%)."

23788912

➶

reach

"XREF_BIBR The successful use of dabrafenib in case of vemurafenib induced severe AEs have been reported."

32066648

➶

reach

"XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR The AEs are also tolerable for those patients treated with dabrafenib when compared with approved therapies for second- and third-line NSCLC."

27080216

Dabrafenib affects NEK9

| 1 2

Dabrafenib inhibits NEK9. 3 / 3

| 1 2

➶

reach

"Dabrafenib, a medication for the treatment of BRAF-associated cancers, is predicted to inhibit NEK9, an interactor of NSP9."

32444466

➶

eidos

"Dabrafenib , a medication for the treatment of BRAF-associated cancers , is predicted to inhibit NEK9 , an interactor of NSP9 ."

32444466

➶

reach

"In cell based studies of NRAS- and KRAS-mutant cancer cells, dabrafenib inhibited the NEK9 target CHK1, whereas vemurafenib did not."

29112787

Dabrafenib affects MCL1

| 3

Dabrafenib increases the amount of MCL1. 3 / 3

| 3

➶

reach

"As observed earlier, dabrafenib at a concentration of 10 nM significantly induced the expression of Mcl-1 in A375, SK-MEL-28, SK-MEL-5 and WM-239 cells."

26497853

➶

reach

"Similar to vemurafenib, we observed that dabrafenib treatment also induced massive Mcl-1 expression at all the three concentrations."

26497853

➶

reach

"Dabrafenib induces Mcl-1 expression in melanoma cells."

26497853

Dabrafenib affects CYP2C9

| 1 2

Dabrafenib activates CYP2C9. 3 / 3

| 1 2

➶

reach

| PMC

➶

reach

"Because dabrafenib induces CYP3A4 and CYP2C9 it decreased the systemic exposures of the CYP3A4 substrate midazolam, the CYP2C9 substrate S-warfarin, and the CYP3A4/CYP1A2 substrate R-warfarin."

| PMC

➶

eidos

"Because dabrafenib induces CYP3A4 and CYP2C9 it decreased the systemic exposures of the CYP3A4 substrate midazolam , the CYP2C9 substrate S-warfarin , and the CYP3A4 / CYP1A2 substrate R-warfarin ."

| PMC

Brivanib affects Liver Cirrhosis

| 3

Brivanib inhibits Liver Cirrhosis. 3 / 3

| 3

➶

medscan

"Our findings demonstrate that brivanib reduces liver fibrosis in three different animal models, and inhibits growth factor-induced stellate cell proliferation and activation."

24710173

➶

medscan

"In this study we have shown that brivanib reduces liver fibrosis in three different animal models through effects on platelet-derived growth factor, VEGF and fibroblast growth factor signaling."

24710173

➶

medscan

"Our results suggest that brivanib inhibits liver fibrosis through effects on multiple signaling pathways."

24710173

Y-39983 affects RHOA

| 3

Y-39983 inhibits RHOA. 3 / 3

| 3

➶

reach

"Similarly, different Rho kinase inhibitors including HA1007 (fasudil), Y-39983 (SJN-1656), ripasudil (K-115) and Y-27632 were found to exhibit neuroprotection by promoting axonal outgrowth and RGC survival in different animal models (Bermel et al., 2009; Hirata et al., 2008; Kitaoka et al., 2004; Sagawa et al., 2007; Sugiyama et al., 2011; Van de Velde et al., 2015; Yamamoto et al., 2014; Yu et al., 2015, 2016)."

27593914

➶

reach

27593914

➶

reach

"More specific Rho kinase inhibitors, such as Y-27632, Y-39983, HA-1077, H-1152 and INS117548, increase outflow facility and/or decrease IOP in living rabbits and monkeys and/or enucleated animal eyes, similar to H-7 [XREF_BIBR - XREF_BIBR, XREF_BIBR - XREF_BIBR]."

22737177

Y-27632 affects PKN2

3 |

Y-27632 inhibits PKN2. 3 / 3

3 |

➶

tas

No evidence text available

20462760

➶

tas

No evidence text available

➶

tas

No evidence text available

12672248

Y-27632 affects Carcinoma, Renal Cell

| 3

Y-27632 inhibits Carcinoma, Renal Cell. 3 / 3

| 3

➶

medscan

"Second, we have shown that the ROCK inhibitor Y-27632 suppresses Clear Cell Renal Cell Carcinoma tumor growth in vivo."

27841867

➶

medscan

"Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 Clear cell renal cell carcinoma tumors in mice."

27841867

➶

medscan

27841867

KW2449 affects FLT3

3 |

KW2449 inhibits FLT3. 3 / 3

3 |

➶

tas

No evidence text available

22037378

➶

tas

No evidence text available

| DOI

➶

tas

No evidence text available

24044867

KW2449 affects DNA Damage

| 3

KW2449 activates DNA Damage. 3 / 3

| 3

➶

reach

"These findings argue that while ROS generation plays a significant functional role in HDACI and KW2449 mediated DNA damage and apoptosis in Bcr and Abl + leukemia cells, additional factors may be involved in lethality."

21474579

➶

reach

"The finding that HDACIs potentiated DNA damage induced by KW2449 (or other Bcr and Abl kinase inhibitors) reflected by increased expression of lambdaH2A.X, a marker for double-strand DNA breaks, has also not been previously described."

21474579

➶

reach

"In view of evidence that Bcr and Abl kinase inhibitors can disrupt DNA repair mechanisms in Bcr and Abl + cells [XREF_BIBR], the effects of HDACIs on KW2449 induced DNA damage was examined."

21474579

KW2449 affects ABL1

1 | 2

KW2449 inhibits ABL1. 3 / 3

1 | 2

➶

reach

"Although the multi-kinase inhibitor KW2449, which also inhibits Bcr and Abl and aurora kinases, has primarily been developed as a FLT3 inhibitor in AML [XREF_BIBR], preclinical studies demonstrate that it effectively kills Bcr and Abl + leukemias, including Ph + ALL, bearing gatekeeper mutations [XREF_BIBR]."

21474579

➶

tas

No evidence text available

22037378

➶

reach

"In IM resistant BV173 and E255K and Adult and T315I cells, coadministration of KW2449 with either vorinostat or SNDX clearly inhibited Bcr and Abl activation and reduced total expression, whereas single drug treatment minimally affected Bcr and Abl levels or activation status."

21474579

A-674563 affects RPS6KB1

2 | 1

A-674563 inhibits RPS6KB1. 3 / 3

2 | 1

➶

tas

No evidence text available

22037378

➶

reach

"Further, A-674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells."

26970307

➶

tas

No evidence text available

A-674563 affects RPS6KA3

3 |

A-674563 inhibits RPS6KA3. 3 / 3

3 |

➶

tas

No evidence text available

16678413

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tas

No evidence text available

22037378

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tas

No evidence text available

A-674563 affects ROCK1

3 |

A-674563 inhibits ROCK1. 3 / 3

3 |

➶

tas

No evidence text available

20006497

➶

tas

No evidence text available

➶

tas

No evidence text available

22037378

A-674563 affects PRKCD

3 |

A-674563 inhibits PRKCD. 3 / 3

3 |

➶

tas

No evidence text available

➶

tas

No evidence text available

16678413

➶

tas

No evidence text available

22037378

A-674563 affects MAPK1

3 |

A-674563 inhibits MAPK1. 3 / 3

3 |

➶

tas

No evidence text available

22037378

➶

tas

No evidence text available

16678413

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tas

No evidence text available

A-674563 affects GSK3B

3 |

A-674563 inhibits GSK3B. 3 / 3

3 |

➶

tas

No evidence text available

22037378

➶

tas

No evidence text available

16678413

➶

tas

No evidence text available

Sotrastaurin affects IL2

| 3

Sotrastaurin decreases the amount of IL2.

| 2

Sotrastaurin decreases the amount of IL2. 2 / 2

| 2

➶

| 1

Dabrafenib activates PTTG1. 1 / 1

| 3

Sotrastaurin inhibits AKT.

| 1

Sotrastaurin inhibits AKT. 1 / 1

| 1

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reach

"To confirm the involvement of PI3Kdelta and PKCbeta in the resistance to ATO, we first studied whether idelalisib and sotrastaurin inhibited the activation of Akt, NF-kappaB and STAT3."

26540567

Sotrastaurin dephosphorylates AKT.

| 1

Sotrastaurin leads to the dephosphorylation of AKT. 1 / 1

| 1

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reach

26540567

Sotrastaurin activates AKT.

| 1

Sotrastaurin activates phosphorylated AKT. 1 / 1

| 1

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reach

"In these cells AEB071 inhibited p-MARCKS and p-S6 but induced activation of p-AKT over time, which was inhibited by BYL719 in the combination therapy."

24563540

Momelotinib affects STAT5

medscan

"AEB071, an inhibitor of protein kinase Cθ kinase activity, also inhibits growth and invasive branching of triple-negative breast cancer cells in 3-D cultures, further supporting a role for protein kinase Cθ kinase activity in triple-negative cancer cell growth."

27663795

➶

medscan

27663795

Sotrastaurin affects superoxide

| 2

Sotrastaurin activates superoxide. 2 / 2

| 2

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reach

"The protein kinase C inhibitor AEB071 (sotrastaurin) modulates migration and superoxide anion production by human neutrophils in vitro."

23058012

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reach

"The protein kinase C inhibitor AEB071 (sotrastaurin) modulates migration and superoxide anion production by human neutrophils in vitro."

23058012

Sotrastaurin affects signaling

| 2

tas

No evidence text available

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tas

No evidence text available

19827831

Sotrastaurin affects Infections

| 2

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reach

32676568

➶

tas

No evidence text available

19762238

Momelotinib affects ACVR1

1 | 1

| 2

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medscan

24710173

➶

medscan

"Our findings demonstrate that brivanib reduces liver fibrosis in three different animal models, and inhibits growth factor-induced stellate cell proliferation and activation."

24710173

Brivanib affects FGF

| 2

| 2

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medscan

"These results suggest that targeting the TGF-β signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human Cholangiocarcinoma."

28873435

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medscan

28873435

KW2449 affects MAP3K11

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KW2449 inhibits MAP3K11. 2 / 2

2 |

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2 |

| 1

Sotrastaurin inhibits Lymphoma, Large B-Cell, Diffuse. 1 / 1

| 1

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medscan

"Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas."

21324920

Sotrastaurin activates Lymphoma, Large B-Cell, Diffuse.

| 1

Sotrastaurin activates Lymphoma, Large B-Cell, Diffuse. 1 / 1

| 1

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| 1

Sotrastaurin decreases the amount of CDKN1B. 1 / 1

| 1

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reach

22653968

Sotrastaurin activates CDKN1B.

| 1

Sotrastaurin activates CDKN1B. 1 / 1

| 1

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| 1

Momelotinib inhibits LY6G6D. 1 / 1

| 1

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reach

30670049

Momelotinib decreases the amount of LY6G6D.

| 1

Momelotinib decreases the amount of LY6G6D. 1 / 1

| 1

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| 1

Dabrafenib inhibits iodide. 1 / 1

| 1

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reach

"Moreover, dabrafenib rather than another clinically used B-Raf inhibitor vemurafenib (with poor RIP3 inhibitory activity) reversed the loss of propidium iodide (PI)-negative HT29 cells caused by TSZ (XREF_SUPPLEMENTARY)."

24901049

Dabrafenib activates iodide.

| 1

Dabrafenib activates iodide. 1 / 1

| 1

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| 1

Dabrafenib binds cobimetinib. 1 / 1

| 1

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reach

"In preclinical studies, there is strong evidence for the interaction of vemurafenib, dabrafenib, trametinib, palbociclib, cobimetinib and omipalisib with P-gp and BCRP."

28546917

Dabrafenib activates cobimetinib.

| 1

Dabrafenib activates cobimetinib. 1 / 1

| 1

| 1

Dabrafenib leads to the phosphorylation of STING1. 1 / 1

| 1

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reach

"As speculated, combined treatment of Dabrafenib or Vemurafenib with diABZI, enhanced phosphorylation of STING (XREF_FIG) and IRF3 (XREF_FIG)."

32477956

Dabrafenib activates STING1.

| 1

Dabrafenib activates STING1. 1 / 1

| 1

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| 1

Dabrafenib leads to the phosphorylation of JNK. 1 / 1

| 1

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reach

"Dabrafenib was found to inhibit apoptosis, and to enhance the phosphorylation of extracellular signal regulated kinase (ERK), and inhibit the phosphorylation of c-Jun NH2-terminal kinase."

30137437

Dabrafenib inhibits JNK.

| 1

Dabrafenib inhibits JNK. 1 / 1

| 1

| 1

Y-27632 inhibits cell differentiation. 1 / 1

| 1

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reach

"However, since differentiated hAEC cultures cannot be reliably established after monolayer passage two due to cellular senescence and loss of differentiation potential [16] we had to devise a method that would prolong the lifespan of primary human cells in monolayer culture to allow for lentiviral transduction, expansion and eventual cell sorting.Treatment of both bronchial and cervical epithelial cells with a commercially available ROCK inhibitor, Y-27632, has been shown to induce a basal epithelial cell phenotype, thereby preserving the differentiation capabilities of human epithelial cells in vitro [18]."

31412613

Y-27632 activates cell differentiation.

| 1

Y-27632 activates cell differentiation. 1 / 1

| 1

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| 1

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medscan

"Consistent with this idea is the observation that ROCK inhibitor Y-27632 reduces hypertension , and that the Ras-homology/ROCK signaling pathway in smooth muscle cells is an important contributor to peripheral resistance ."

21885830

Y-27632 inhibits Hypertension. 1 / 1

| 1

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eidos

"Y-27632 also suppresses formation of stress fibers in cultured cells and decreases hypertension in several hypertensive rat models [ 109,110,111 ] ."

32560459

LY-2157299 affects angiogenesis

| 1 1

LY-2157299 activates angiogenesis. 1 / 1

| 1

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reach

"In vivo, LY-2157299 induced angiogenesis and enhanced VEGF- and basic-fibroblast-growth-factor-induced angiogenesis in a Matrigel-plug assay, whereas adding an alpha5-integrin-neutralizing antibody to the Matrigel selectively inhibited this enhanced response."

19706683

LY-2157299 activates angiogenesis. 1 / 1

KW2449 inhibits apoptotic process. 1 / 1

| 1

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reach

"KW2449 significantly reduced the viability of wildtype-PTEN cells causing apoptosis, while little effect was observed in mutant-PTEN counterparts."

30118842

KW2449 activates apoptotic process.

| 1

KW2449 activates apoptotic process. 1 / 1

| 1

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reach

"KW2449 interacts synergistically with HDACIs to induce apoptosis in Ph + CML cells in a time- and concentration dependent manner."

21474579

KW2449 affects Histone_H3

| 2

KW2449 dephosphorylates Histone_H3.

| 1

KW2449 leads to the dephosphorylation of Histone_H3. 1 / 1

| 1

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reach

23433459

Sotrastaurin affects cPKC

| 1

Sotrastaurin inhibits cPKC. 1 / 1

| 1

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reach

"One of the most potent and clinically advanced PKC inhibitors is AEB071, which selectively inhibits cPKC and nPKC isoforms."

26420215

Sotrastaurin affects branching

| 1

| 1

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reach

30891031

Sotrastaurin affects Tconv

| 1

Sotrastaurin inhibits Tconv. 1 / 1

| 1

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reach

"However, AEB071 was fully able to suppress Tconv activation when included in the cultures throughout, implying a reversibel nature of AEB071."

28531229

Sotrastaurin affects TCR

| 1

Sotrastaurin inhibits TCR. 1 / 1

| 1

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reach

27780854

Sotrastaurin affects TBK1

| 1

Sotrastaurin inhibits TBK1. 1 / 1

| 1

| 1

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reach

"In particular, although AEB071 downregulated A3B expression, this was not the case for MYBL2, indicating that at least two parallel signal pathways act synergistically to regulate A3B expression in human cells (XREF_FIG)."

28276478

Sotrastaurin affects S473-Akt

| 1

Sotrastaurin leads to the dephosphorylation of S473-Akt. 1 / 1

| 1

| 1

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reach

"Since it reportedly does not inhibit Ca 2+ signaling, combination therapy with other immunosuppressive agents such as cyclosporine A at low, suboptimal concentrations may be useful, provided it does not cause global, potentially harmful immunosuppression It has been argued that the ability of AEB071 to broadly inhibit PKCs underlies its inhibition of T cell activation, since this broad activity prevents potential compensation by other PKC isoforms."

23433459

Sotrastaurin affects PKCetaat

| 1

1 |

➶

tas

No evidence text available

Sotrastaurin affects Melanoma

| 1

Sotrastaurin activates Melanoma. 1 / 1

| 1

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medscan

"protein kinase C inhibition with AEB071 or AHT956 suppressed protein kinase C and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations."

24141786

Sotrastaurin affects MST1R

1 |

Sotrastaurin inhibits MST1R. 1 / 1

1 |

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tas

No evidence text available

Sotrastaurin affects MSC

| 1

Sotrastaurin inhibits MSC. 1 / 1

| 1

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reach

"Addition of tacrolimus, rapamycin or sotrastaurin to the lysis assay did not inhibit MSC killing."

21732766

Sotrastaurin affects MINK1

1 |

Sotrastaurin inhibits MINK1. 1 / 1

1 |

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tas

No evidence text available

Sotrastaurin affects MDM2-p53

| 1

Sotrastaurin binds MDM2-p53. 1 / 1

| 1

| 1

1 |

➶

tas

No evidence text available

Sotrastaurin affects EIF4EBP1

| 1

Sotrastaurin leads to the dephosphorylation of EIF4EBP1. 1 / 1

| 1

➶

reach

"Sotrastaurin decreased the expression of pro survival protein myeloid cell leukemia (MCL-1) and the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), both of which are downstream effectors of PIM-1."

30017192

Sotrastaurin affects EIF4E

| 1

1 |

➶

tas

No evidence text available

Sotrastaurin affects CAMK2D

1 |

| 1

➶

reach

26443648

Recombinant hPXR affects dabrafenib

| 1

| 1

➶

reach

26443648

Nilotinib affects dabrafenib

| 1

➶

eidos

31662325

Momelotinib affects RIOK3

1 |

Momelotinib inhibits RIOK3. 1 / 1

1 |

➶

tas

No evidence text available

Momelotinib affects Phosphorylation

| 1

Momelotinib inhibits Phosphorylation. 1 / 1

| 1

➶

sparser

"Phosphorylation of STAT1 Y701 and STAT5 Y694 was inhibited by momelotinib and ruxolitinib (Figure xref )."

29163799

Momelotinib affects NFkappaB

| 1

Momelotinib inhibits NFkappaB. 1 / 1

| 1

➶

eidos

28642467

Momelotinib affects MYLK4

1 |

| 1

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reach

"Momelotinib inhibits ACVR1 and ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents."

28188131

Momelotinib affects ERK

| 1

Momelotinib activates ERK. 1 / 1

| 1

| 1

➶

reach

"The small molecule inhibitors vemurafenib and dabrafenib selectively bind the active conformation of BRAF and inhibit signal transduction between BRAF and MEK."

26174532

Dabrafenib affects robust apoptosis cancer cells harboring BRAF V600E TERT mutations

| 1

Dabrafenib activates robust apoptosis cancer cells harboring BRAF V600E TERT mutations. 1 / 1

| 1

| 1

➶

medscan

27028853

Dabrafenib affects cuSCC/KA

| 1

Dabrafenib inhibits cuSCC/KA. 1 / 1

| 1

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reach

"Indeed, a second clinical grade RAF inhibitor, dabrafenib, effectively inhibits mutant BRAF signaling, elicits strong clinical responses in patients but also induces the formation of cuSCC/KA."

23490205

Dabrafenib affects complete response

| 1

| 1

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reach

27458080

Dabrafenib affects axitinib

| 1

1 |

| 1

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medscan

"To date, two popular second-generation BRAF inhibitors, dabrafenib and vemurafenib, have shown the promising efficacy in patients with BRAF V600E-mutant non-small-cell lung cancer. 46999999="V600E"}"

28135039

Dabrafenib affects SRMS

1 |

➶

reach

30605687

Dabrafenib affects PPP1R13L

| 1

Dabrafenib activates PPP1R13L. 1 / 1

| 1

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reach

"Selumetinib (a selective MEK inhibitor) and dabrafenib (a selective BRAF inhibitor used in BRAF mutated tumors) have been shown to increase RAI uptake by RAI-refractory tumor tissues XREF_BIBR, XREF_BIBR, and these encouraging results are now under investigation (NCT02393690 and NCT03244956)."

29399330

Dabrafenib affects PPARG

| 1

Dabrafenib binds PPARG. 1 / 1

| 1

| 1

➶

reach

"While the combination of dabrafenib and trametinib caused a PR of the patient 's melanoma, at 12 weeks the patient presented with a brain metastasis that, upon resection, was characterized as originating from a KRAS mutated colon cancer."

24957944

Dabrafenib affects PERK12

| 1

Dabrafenib activates PERK12. 1 / 1

| 1

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reach

"Lapatinib blocked the superactivated HER2 and HER3, AKT and pERK1/2 induced by dabrafenib."

28423638

Dabrafenib affects PDCD1

| 1

reach

27458080

Dabrafenib affects HR

| 1

Dabrafenib activates HR. 1 / 1

| 1

➶

reach

"In two randomized phase III trials, the combination of dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and OS compared with either vemurafenib monotherapy (PFS : HR, 0.61; p <.001; and OS : HR, 0.66; p <.001) or dabrafenib plus placebo (PFS : HR, 0.67; p =.0004; and OS : HR, 0.71; p =.0107) in patients with previously untreated, unresectable BRAF V600-mutant melanoma [14], [38]."

28487464

Dabrafenib affects HK2

| 1

Dabrafenib inhibits HK2. 1 / 1

| 1

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reach

24469106

Dabrafenib affects GPT

1 |

Dabrafenib increases the amount of GPT. 1 / 1

1 |

➶

ctd

No evidence text available

27458080

Dabrafenib affects GLUT1

| 1

| 1

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reach

27536070

Dabrafenib affects CSK

1 |

| 1

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reach

27025703

Dabrafenib affects CRAF-CIBN fusion proteins

| 1

Dabrafenib increases the amount of CRAF-CIBN fusion proteins. 1 / 1

| 1

| 1

➶

reach

"In cell based studies of NRAS- and KRAS-mutant cancer cells, dabrafenib inhibited the NEK9 target CHK1, whereas vemurafenib did not."

29112787

Dabrafenib affects CDKN1B

| 1

Dabrafenib activates CDKN1B. 1 / 1

| 1

| 1

➶

medscan

24710173

Brivanib affects PDGFRB

| 1

Brivanib inhibits PDGFRB. 1 / 1

| 1

➶

medscan

24710173

Brivanib affects PDGF

| 1

| 1

➶

eidos

23680019

Y-27632 affects tongue squamous cell carcinoma

| 1

Y-27632 inhibits tongue squamous cell carcinoma. 1 / 1

| 1

➶

medscan

"The study concludes that Y-27632 can inhibit the growth, invasion, and migration of Tca8113 and CAL-27 cells, suggesting that Y-27632 may be therapeutically useful in tongue squamous cell carcinoma."

26468018

Y-27632 affects survival

| 1

medscan

22842919

Y-27632 affects contractile force tracheal smooth muscle guinea pig

| 1

Y-27632 inhibits contractile force tracheal smooth muscle guinea pig. 1 / 1

| 1

➶

eidos

"Further studies suggest one of the important mechanisms that Mfge8 could suppress contraction of airway smooth muscles through inhibiting RhoA.66 Sphingosine-1-phosphate ( S1P : a bioactive lysophospholipid ) has been shown to increase the contraction tension in isolated BSM tissues when they are pre-depolarised by K + , and was attenuated by Y-27632.67Similarly , S1P markedly enhanced contractile force of tracheal smooth muscle in guinea pig , which was also inhibited by Y-27632 ."

32355562